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1. Introduction
The prevalence of chronic kidney disease (CKD) is constantly growing [1] largely due to the shift in age distribution of the population toward individuals older than 60 years, in which CKD is more common, accounted for by the combined effect of physiologic decline in glomerular filtration rate (GFR) and systemic atherosclerosis, and also due to increasing prevalence of arterial hypertension, diabetes mellitus, and obesity, all risk factors for CKD. Notably, the mortality of CKD patients is higher than their non-CKD counterparts, predominantly with respect to cardiovascular mortality. Abnormalities of arterial and left ventricular functions, such as arterial stiffness, atherosclerosis and arteriosclerosis, left ventricular hypertrophy, and systolic and end-diastolic stiffness, which are common in CKD patients, were incriminated [2]. The pathophysiology of cardiovascular disease (CVD) in CKD is complex, with both traditional and uremia-related risk factors being involved. Among the latter, calcium-phosphate metabolism anomalies are more and more debated, and the concept of chronic kidney disease-mineral and bone disorder (CKD-MBD) has been adopted. It is a broad term that refers to a systemic disorder of mineral metabolism due to the kidneys’ failure to maintain homeostasis of calcium (Ca), phosphate (PO4), and active vitamin D, which leads to maladaptive alterations in related hormones, namely fibroblast growth factor-23 (FGF23) and parathyroid hormone (PTH), and results in defective bone architecture and extraskeletal calcifications [3, 4]. CKD-MBD occurs early in the course of CKD, progresses as kidney function declines, and it is manifested by three separate, but interrelated, components that are not necessarily present concurrently in all patients, any combination of these component being possible [4]:
Changes in biochemistry profile (Ca, PO4, vitamin D, PTH, FGF23, and alkaline phosphatase—ALP), which reflect mineral and hormonal abnormalities;
Bone abnormalities regarding turnover, mineralization, volume, linear growth, or strength; and
Soft tissue (vascular, valvular, and periarticular) calcifications.
The vascular calcifications at least partially account for increased cardiovascular (CV) risk in CKD patients, so it is worth to draw attention on the mechanisms involved in their development.
2. Types and characteristics of vascular calcification in chronic kidney disease
Even at early ages, CKD patients develop vascular calcifications at all the levels (large vessel arteries such as the aorta, medium arteries like the coronary arteries, as well as small-caliber arteries of the skin), in a much greater proportion than the general population, and the prevalence and severity of arterial and valvular calcifications increase as kidney function decreases [5].
The main types of arterial calcifications, both commonly seen in CKD, are distinguished by their location in the structure of the arterial wall (Figure 1) and their association with atherosclerotic plaque formation:
Atherosclerosis consists in the calcification of the intimal layer in association with cellular necrosis, inflammation, atherosclerotic plaques, and lipid deposition [6]. This type of calcification is related to traditional risk factors such as arterial hypertension and dyslipidemia (Table 1). The vessel lumen is eccentrically reduced and deformed due to patchy calcification of the atherosclerotic plaques [7]. It produces arterial stenosis which accounts for tissular ischemia and infarction and may predispose to plaque rupture generating life-threatening thrombi.
Arteriosclerosis, which represents the calcification of the medial layer, occurs in the elastic lamina of large-caliber and medium- to small-size arteries. It seems to be independent of atherosclerosis, although both can coexist [6, 7]. Medial calcification was known initially as Mönckeberg’s sclerosis, and it has radiographically been described as “railroad tracks” on the peripheral arteries of upper and lower limbs [6, 8]. This type of calcification is related to non-traditional risk factors such as hyperphosphatemia, excess PTH, and cytokines of chronic inflammation (Table 1), and it is more prevalent in patients with CKD and diabetes [6]. The vessel lumen is reduced concentrically due to amorphous mineral that forms circumferentially along or within one or more elastic lamellae of the media [7]. It induces arterial stiffness, which contributes to increased pulse pressure and, consequently, to left ventricular hypertrophy and altered coronary perfusion [9, 10].
Figure 1.
Main types of arterial calcifications and their consequences. VSMCs, vascular smooth muscle cells.
Traditional risk factors
Non-traditional (CKD-related) risk factors
Arterial hypertension
Hyperphosphatemia, high calcium-phosphate product
Dyslipidemia
Hyper- or hypoparathyroidism
Diabetes mellitus
High dosage of vitamin D metabolites
Smoking
Chronic inflammation
Old age
Oxidative stress
Family history of premature coronary heart disease
Risk factors for vascular calcification in chronic kidney disease patients (modified from Román-García et al. [5]).
CKD: chronic kidney disease.
These two types of calcifications encountered in CKD also vary based on their localization on the arterial tree. Intimal calcifications are found more proximally, while medial ones have a predilection for distal sites [10].
Etiologically, vascular calcifications may be categorized as metastatic calcifications, those which arise from systemically high calcium and phosphate product, or dystrophic calcifications, which take place under pathologic conditions of cell death or apoptosis [9]. Metastatic calcifications occur when the calcium-phosphate product exceeds its solubility in serum resulting in its deposition in healthy, extraskeletal tissue such as the arterial wall, the viscera, the conjunctiva, articulations, or tumors [8]. In contrast, dystrophic calcifications result from the de novo deposition of calcium and phosphate in diseased or damaged tissue. This occurs when cells die as a result of direct injury or apoptosis and release their intracellular calcium contents which can serve as a foundation for further calcium deposition [8].
3. Pathogenesis of vascular calcifications in chronic kidney disease
3.1. Overview on the molecular basis of mineralization and vascular calcifications
Although not yet entirely elucidated, the process of vascular calcification was extensively studied and the bulk of its steps were unveiled. The common feature to almost all physiologic mineralization mechanisms, either inside the bone or in extra-osseous tissues, involves matrix vesicles, which form the nidus for hydroxyapatite crystals nucleation [11]. These matrix vesicles are membrane-bound particles of 20–200 nm where mineral crystals are arranged by interaction with specific regulators, like membrane transporters and enzymes, with crucial roles in the influx of calcium and phosphate ions into the vesicles [9]. For example, tissue nonspecific alkaline phosphatase hydrolyzes pyrophosphate and generates inorganic phosphate, which is further transported through the vesicle membrane by the sodium-phosphate cotransporter type III [12]. On the other hand, annexins function as ion channels and provide a way for calcium to enter inside the matrix vesicle, where the accumulation of both divalent ions induces crystalline nucleation [9, 12].
In the bone, matrix vesicles bud off from the plasma membrane of chondrocytes or osteoblasts, at the epiphyseal plate of growing bone and are released into the premineralized organic matrix where they serve as a vehicle for the interaction of calcium and phosphate ions to form hydroxyapatite and initiate mineralization of the organic substance [11]. Hydroxyapatite crystals that are released from vesicles serve as templates for subsequent crystal formation, creating the lattice of the bone [9, 13]. Therefore, matrix vesicles have an osteogenic role.
Growing body of evidence supports significant resemblance between bone and vascular calcifications, leading to the belief that ectopic calcifications and normal osteogenesis are driven alike. Indeed, many cellular and molecular signaling processes are identical in vascular calcification and osteogenesis. Among these, matrix vesicle release and expression of mineralization-regulating proteins by vascular smooth muscle cells (VSMCs) are seen in the vessel wall [14]. Consequently, vascular calcification is also considered a regulated biomineralization process.
The balance among promoters and inhibitors of calcification plays the key role during mineralization (Figure 2).
Figure 2.
Regulating molecules of the mineralization/calcification processes. RANKL, receptor activator of nuclear factor-kB ligand; (+), stimulation; (−), inhibition.
The main known inhibitor molecules involved in both bone and extra-osseous sites calcification, are:
Matrix GLA protein (MGP, matrix γ-carboxyglutamate protein), an extracellular protein has roles in normal bone formation as well as inhibition of vascular calcification [15, 16]. The inactive MGP (desphospho-uncarboxylated MGP, dp-ucMGP) needs two subsequent modifications (serine phosphorylation and glutamate carboxylation) in order to exert its function [17]. Circulating levels of dp-uc MGP are considered a biomarker associated with cardiovascular risk and mortality, severity of the vascular damage, and all-cause mortality [17]. MGP is able to bind calcium and hydroxyapatite, thanks to its vitamin K-dependent γ-carboxylation, inhibiting their precipitation and mineralization [16]. MGP synthesis has been detected in cartilage, lung, heart, kidney, arteries, and calcified atherosclerotic plaques attesting to MGP’s role in inhibition of soft tissue calcifications [18]. In addition, recent works suggested a link between MGP and renal microvasculature, and argued in favor of a possible renoprotective action of activated MGP and, consequently, emphasized the importance of having adequate vitamin K stores [17].
Osteoprotegerin (OPG) is a soluble cytokine and tumor necrosis factor (TNF) receptor-like molecule that acts as an inhibitor of osteoclast differentiation by binding the receptor activator of nuclear factor κB-ligand (RANKL), thus blocking RANKL-mediated activation of osteoclasts [11, 19]. OPG is present in many human tissues: bone (osteoblasts), vessels (endothelial and vascular smooth muscle cells), lung, heart, liver, kidney, hypothalamus, lymphoid organs and B-cells, bone marrow, articular chondrocytes, and breasts [19, 20]. Its expression in bone is regulated by osteoblasts through the same pathway that regulates bone formation, indicating RANKL/OPG ratio is a major determinant of bone mass and OPG has an osteoprotective role [21]. However, its functions in the vascular system are still a matter of debate. While experimental studies sustain an anti-calcification role (due to inhibition of apoptotic passive calcification and the alkaline phosphatase-mediated osteogenic differentiation of vascular cells), elevated serum levels of OPG were found in various cardiovascular diseases and were hypothesized as a promoter of atherosclerosis progression [19]. Osteoprotegerin expression was significantly lower and RANKL was identified in calcified valves of human aortic stenosis, indicating that in the absence of inhibition by OPG, RANKL may promote matrix calcification and induce the expression of osteoblast-associated genes (bone alkaline phosphatase and osteocalcin) [22].
Extracellular pyrophosphate (PPi) is a small molecule made of two phosphate ions linked by an ester bond, which regulates cell differentiation and serves as an essential physiologic inhibitor of calcification by negatively interfering with hydroxyapatite formation and crystal growth [11]. PPi is produced from the hydrolyses of extracellular adenosine-5′-triphosphate by the enzyme ectonucleotide pyrophosphatase/phosphodiesterase [23]. On the other hand, alkaline phosphatase (ALP) catalyzes the hydrolysis of phospho-monoesters (including PPi) with release of inorganic phosphate (Pi) in order to avoid accumulation of this mineralization inhibitor, thus ensuring normal bone mineralization [11, 24]. However, through this action, ALP also acts as a powerful inducer of vascular calcification partially as a result of increased PPi degradation [23].
Fetuin-A, a circulating glycoprotein from the cystatin superfamily of proteins, produced by the liver, functions as a potent inhibitor of de novo hydroxyapatite formation from supersaturated mineral solutions, and it also acts as a negative acute phase reactant, thus being downregulated in acute and chronic systemic inflammation [25, 26, 27]. In experimental and clinical studies, it was shown that serum containing fetuin-A inhibited precipitation of calcium salts in a dose-dependent manner, and its serum concentrations were inversely correlated to C-reactive protein, calcifications, and cardiovascular and all-cause mortality, even when the serum calcium-phosphate product was close to the normal range [26, 28]. Hence, it was assumed that a major link between low fetuin-A levels and mortality consists of promoting accelerated cardiovascular calcification [26].
Other main factors with essential contribution to the processes of mineralization and calcification are those involved in the signaling pathways, like:
Bone morphogenetic proteins (BMPs) are cytokines with multiple functions, which modulate gene expression through phosphorylation of regulatory Smad transcription factors [16, 27]. Smad6 and Smad7 proteins act as negative regulators and thus are crucial to limit the osteogenic vascular response induced by BMPs [27]. For example, BMP 2—a protein that belongs to the transforming growth factor-β (TGF-β) superfamily of cell regulatory proteins—is involved in both osteogenic and chondrogenic differentiation of multipotent mesenchymal progenitors and drives the formation of cartilage and bone [29]. It also participates in vascular calcification probably through inducing osteoblastic differentiation of VSMCs. Conversely, BMP 7, primarily expressed in the kidney where it is required for the normal development of the organ, was found to restore the bone anabolic balance, reduce serum phosphate levels, and reduce vascular calcification [27].
Core-binding factor alpha 1 (Cbfa1), also known as runt-related transcription factor 2 (Runx2), is a nuclear protein essential for osteoblastic development and skeletal morphogenesis, and it is believed to be the switch that turns a mesenchymal cell into an osteoblast [11, 13, 30]. It acts as a scaffold for the interaction of nucleic acids and regulatory factors that are involved in the expression of a number of downstream proteins essential for osteoblastic differentiation, such as type I collagen, osteocalcin, and osteopontin [13].
Type I collagen makes up over 90% of the organic component of bone where it forms the framework necessary for mineralization [13, 31]. It was shown that ex vivo cells grown on type I collagen were found to mineralize three times faster and incorporate two times more calcium than cells grown in plastic media. Moreover, rapidly mineralizing cells generate a matrix that contains three times the amount of collagen type I and fibronectin but 70% less collagen type IV than their non-mineralizing counterparts. These findings indicate a regulatory role of the matrix composition on arterial calcification development [31].
Osteocalcin is a protein secreted by active osteoblasts into the extracellular matrix where it binds hydroxyapatite via 3 γ-carboxylated glutamic acid residues during bone mineralization. For this reason, it is often used as a marker for bone formation [32].
Osteopontin, also known as secreted phosphoprotein 1 or bone sialoprotein 1, is an extracellular structural component of bone (of the non-collagenous organic bone matrix) and an important modulator of bone mineralization, which can either promote or inhibit hydroxyapatite formation, depending on its post-translational modifications [11, 15]. Non-phosphorylated osteopontin shows a stimulatory effect on calcification, while phosphorylation of osteopontin converts it into a potent inhibitor of ectopic calcifications, proportional to the number of phosphorylated sites [33]. Overexpression of osteopontin was found in human atherosclerotic plaques, in calcified smooth muscle cells, in medial layers of arteries of diabetic patient, and calcified heart valves, suggesting it intervenes in the development of ectopic calcifications [34].
In conclusion, mineralization and calcification processes are tightly regulated through the complex interactions of various tissular and circulating molecules, many of which suffer profound changes in chronic kidney disease.
3.2. How does chronic kidney disease favor vascular calcifications?
3.2.1. Imbalance between pro- and counter-calcification factors
Vascular calcifications in CKD patients are thought to arise due to disruptions in the balance between promoters and inhibitors of calcification, leading to osteoblastic transformation of vascular smooth muscle cells (VSMCs) [5, 35]. Because VSMCs and osteoblasts derive from a similar mesenchymal cell precursor, VSMCs can be induced to differentiate along osteoblastic lines. The process involves an increase in calcification promoters, decrease in calcification inhibitors, and formation of calcification vesicles culminating with the induction of a cellular phenotypic change from VSMCs to osteoblast-like cells [5].
Concerning promoters of calcification, it is recognized that the osteoblastic differentiation, which is the initial step in vascular calcification, is revealed by the expression of pro-calcification factors such as Cbfa1 and BMP on vascular cells [13, 15]. In vitro experiments showed that changes in serum composition like those that occurred in the course of CKD may upregulate expression of Cbfa1, while in vivo studies found higher expression of Cbfa1 in both the media and intima of calcified arteries compared to non-calcified arteries of the same patients, thus emphasizing the important role of Cbfa1 in vascular calcifications [5, 36]. In addition, since positive immunostaining for bone matrix proteins (like osteonectin, osteopontin, bone sialoprotein, alkaline phosphatase, and type I collagen) were more common than overt calcifications but were proportional with their extent, it appears that the deposition of these proteins precedes calcification [36]. Another modulator of calcification—osteocalcin—has been detected in VSMCs where it may potentially regulate their glucose utilization, promoting a phenotypic change in these cells [32]. Furthermore, an inverse correlation between osteopontin plasma levels and glomerular filtration rate (GFR) was reported, suggesting that reduced renal excretion due to impaired kidney function may lead to increased circulating levels [37]. Increased osteopontin and other promoters of calcification in CKD can be accounted for by different mechanisms also. For example, in experimental settings, high concentrations of phosphorus, uremic serum, oxidized lipids, cytokines, and high glucose (abnormalities commonly seen in CKD patients as well) were able to stimulate the VSMCs and vascular pericytes to produce bone-forming transcription factors and proteins [36]. Taken together, these findings suggest that biochemical changes that occur during the progression of CKD (hyperphosphatemia, hypercalcemia, accumulating uremic toxins, cytokines, oxidized lipoproteins, and advanced glycation end products) tip the balance in favor of promoters of vascular calcification.
On the other hand, abnormalities of calcification inhibitors can also contribute to the pathogenesis of vascular calcifications in CKD. For example, lower levels of matrix Gla protein were associated with decreased kidney function, probably because metabolic abnormalities due to CKD, such as vitamin D deficiency, may suppress MGP production. Alternatively, MGP may be lost from circulation as it binds to hydroxyapatite crystals in vascular calcifications. Regardless of the mechanism, reduced plasma MGP has been suggested as a marker for the presence and severity of vascular calcifications in patients with CKD [38]. Also, lower levels of circulating fetuin-A were described in CKD and were associated with coronary artery calcification, valvular calcifications, and increased mortality in dialysis patients [36].
These changes in the levels of both promoters and inhibitors of vascular calcification, that occur in CKD patients, ultimately culminate in the transdifferentiation of VSMCs to an osteoblast phenotype through an active, cell-mediated, osteogenic process, with the release of calcium matrix vesicles that can nucleate hydroxyapatite and form the first nidus for calcification [11, 30]. The process is driven by upregulation of bone-forming transcription factors and proteins on VSMCs, such as Cbfa1 and bone morphogenetic protein 2, which control the expression of osteogenic proteins (osteocalcin, osteonectin, alkaline phosphatase, collagen type I, and bone sialoprotein). Exposure to high levels of calcium, phosphate, cytokines, and so on, along with the deficit of calcification inhibitors (such as fetuin-A, matrix Gla protein, pyrophosphate) are required for the cells’ phenotypic switch [39]. The transformed cells deposit collagen and non-collagenous proteins in the arterial wall and incorporate calcium and phosphorus into matrix vesicles to initiate mineralization and crystal growth. The overall positive calcium and phosphorus balance from CKD patients supports both the cellular transformation and the generation of matrix vesicles [36].
3.2.2. Mineral metabolism abnormalities and vascular calcifications
Elevated calcium levels have long been implicated in the vascular calcifications observed in CKD patients. Early on, these patients are usually hypocalcemic as a result of calcitriol deficiency, but treatment with calcium salts and vitamin D derivatives can induce a positive calcium balance or even overt hypercalcemia [30]. In this context, it is possible that in patients with advanced kidney disease, calcium that is absorbed from the gastrointestinal tract cannot be excreted by the failing kidneys nor can it be deposited in bones with altered turnover (either high or low turnover is detrimental) and is therefore deposited at extra-osseous sites, such as the vascular bed [5, 6]. Calcium changes in the external milieu have a direct effect on the nearby cells. Normally, VSMCs recognize these changes via the membrane such as calcium sensing receptor (CaR) and a G-protein-coupled receptor, which was shown to be downregulated in calcified arteries from CKD patients, suggesting that calcium sensing is disrupted in these patients [6, 40]. In response to elevated extracellular calcium, VSMCs release calcium-laden vesicles, as an attempt to prevent intracellular calcium overload. When the vesicles do not contain enough calcification inhibitors (as in CKD), this adaptive response in fact promotes extracellular matrix calcification by serving as a site of origin for propagated calcification [35].
Besides calcium, hyperphosphatemia that is so common in advanced CKD, has emerged as a major culprit of vascular calcifications [41]. Increased serum levels of phosphate induce osteoblastic transformation of VSMCs, while the decrease of phosphatemia reduces the expression of proteins responsible for active bone mineral deposition in vascular cells [15, 35]. As suggested by in vitro studies, phenotypic transformation of VSMCs in response to hyperphosphatemia is mediated by Pit-1 (a type III sodium-phosphate cotransporter), which allow the influx of phosphate into VSMCs and predisposes the cells to undergo mineralization. It was observed that the first step of vascular calcification requires an increased uptake of calcium and phosphate by the VSMCs [42].
In addition to sodium-phosphate cotransport, alkaline phosphatase is necessary for the uptake of phosphorus into the cell and the subsequent induction of osteopontin. Moreover, VSMCs treated with pooled uremic sera from CKD patients also increased expression of osteopontin and mineral deposition, suggesting that uremic serum plays a role in vascular calcifications [43].
Clinical data also support the link between elevated phosphate and vascular calcifications. For example, in a population-based cohort without CKD, serum phosphate levels at the upper end of normal range were associated with aortic valve sclerosis and mitral annular calcification, independent of PTH or calcium values [44]. Moreover, each 1 mg/dL increase in serum phosphate appears to predict higher risk for de novo coronary artery calcification (CAC) over time, with an impact similar to traditional cardiovascular risk factors, in relatively healthy subjects [45]. As in general population, phosphate serum concentration correlated with a greater risk of ectopic calcification in patients with moderate CKD (stage 3), as each 1 mg/dL increase in phosphatemia, even within normal laboratory ranges, was associated with a 21, 33, 25, and 62% higher prevalence of coronary and thoracic arteries, aortic and mitral valves calcifications, respectively [46].
Furthermore, in the presence of increased phosphate, even modest increases in calcium can substantially exacerbate calcification, by inducing nucleation of basic calcium-phosphate and, consequently, the growth of nascent vesicles that are released from both viable and apoptotic VSMCs [47]. The dominant role of phosphate is further supported by experimental studies which showed that dietary phosphate restriction in FGF23-null mice (an animal model characterized by hyperphosphatemia, markedly elevated circulating calcitriol levels, extensive vascular calcifications, and early mortality) yielded complete resolution of ectopic calcifications, a result which was not obtained with the vitamin D-deficient diet [48].
The relationship between vitamin D and vascular calcification appears to follow a biphasic dose-response curve, with adverse effects associated with very high and very low calcidiol levels [49]. At certain levels, vitamin D promotes bone formation by increasing the expression of critical matrix proteins in osteoblasts, leading to the incorporation of calcium into bone, thus taking it away from the vasculature. In addition, vitamin D may also prevent vascular calcifications through modulation of inflammatory responses [50]. Indeed, in dialysis patients, serum levels of calcidiol were inversely correlated with the extent of coronary calcifications [51], and clinical observations revealed that vitamin D receptor agonists were associated with decreased deposition of calcium, improved therapeutic outcomes, and survival benefits, independent of baseline levels of calcium, phosphate, parathyroid hormone, measured comorbidities, and kidney function [6, 15, 52].
However, vitamin D excess was associated with medial calcification and arterial stiffness [49]. Indeed, high doses of vitamin D may actually increase the risk of vascular calcification in CKD owing to its effects on increasing intestinal calcium and phosphate absorption, as well as the mobilization of these minerals from bone, leading to hypercalcemia and hyperphosphatemia, especially in patients already taking calcium-based phosphate binders [13, 50, 52]. Besides its indirect effects due to interactions with the other major factors involved in osteoblastic transformation of VSMCs, vitamin D appears to directly induce the phenotypic switch through the vitamin D receptors on VSMCs resulting in upregulation of proteins involved in calcium transport and mineralization such as osteopontin and osteocalcin [35, 53].
Taken together, these data suggest that excess calcitriol can promote vascular calcifications through several interrelated mechanisms, while moderate physiological or pharmacological doses are beneficial (by suppressing the expression of osteoblastic genes in VSMCs). Debate also exists concerning the potential differential effects and benefits of native vitamin D as compared to active vitamin D receptor agonists, with an assumption that early administration of nutritional supplementation in CKD patients may prevent vascular calcification [54]. However, this remains to be proven by future research.
Secondary hyperparathyroidism may also be involved, indirectly, in the osteoblastic transformation of VSMCs since its excessive action on bone resorption results in hypercalcemia and hyperphosphatemia [55]. Also, arterial hypertension which may result from persistently increased parathyroid hormone (PTH), through the stimulation of renin-angiotensin-aldosterone and sympathetic nervous systems, is another indirect pathway to endothelial dysfunction and arterial calcification [56]. Despite these pathogenetic links, the exact contribution of PTH on vascular calcification is not known yet. In various clinical trials, therapies directed to decrease PTH (parathyroidectomy and calcimimetics) provided discordant results on prevention or regression of vascular calcifications [57, 58, 59]. Moreover, both hyperparathyroidism (which induce high bone turnover and activation of osteoclasts with calcium and phosphorus release into the circulation) and suppressed PTH (which induce adynamic bone disease with low bone turnover and reduce uptake of calcium and phosphate into the bone) were associated with extensive arterial calcifications [60]. Consequently, it was hypothesized that parathyroid hormone does not exert a direct intervention in the pathogenesis of vascular calcification in CKD, so its exact role on this matter remains to be elucidated.
The relationships of Fibroblast growth factor 23 (FGF23) and its receptor—Klotho—with calcifications were also investigated, but conflicting results were reported. Some authors found an association of increased FGF23 with carotid artery calcification in stages 3 and 4 CKD patients [61], and with abdominal aortic calcifications in hemodialysis patients [62], while others observed contrary findings [63]. To date, it is not clear whether FGF23 can directly act on vascular cells to promote or inhibit matrix calcification. It is possible that the involvement of FGF23 in vascular calcification would be only indirect, through the related calcium-phosphate metabolism disturbances [64]. Alternatively, since FGF23 needs Klotho as mandatory co-receptor and Klotho (which controls the dedifferentiation of VSMCs by blocking the expression sodium-phosphate cotransporters) decreases from the early stages of CKD, the ability of FGF23 to interact with vascular cells is consequently altered [64, 65]. Despite the fact that experimental data are congruent to suggest that the effect of Klotho is protective against vascular calcifications, it still remains unknown whether or not Klotho is expressed in the vessel wall [64]. Thus, no definitive conclusions regarding the direct effects of FGF23 or Klotho on VSMCs functions can be drawn based on the current state of knowledge.
4. Clinical consequences of vascular calcifications in chronic kidney disease
Observational studies point to cardiovascular disease (CVD) as the leading cause of morbidity and mortality in CKD patients. The annual 2014 report of the United States Renal Data System estimates that, in patients with CKD, the prevalence of CVD is 69.8% compared to 34.8% in patients without renal disease, and these numbers increase with decline in kidney function [66]. In fact, the risk of any cardiovascular (CV) event seems to increase as estimated glomerular filtration rate (eGFR) decreases, ranging from a 43% increase in risk with an estimated GFR of 45–59 mL/min/1.73 m2 to a 600% increase in cardiovascular (CV) risk at an estimated GFR of less than 15 mL/min/1.73 m2 [67].
The burden of CVD in patients with CKD is, at least in part, accounted for by the presence of non-traditional risk factors, which are much more prevalent in this group. Among these, mineral metabolism abnormalities and vascular calcifications are commonly seen. For example, Russo et al. reported that 40% of patients with stage 3 CKD had coronary artery calcification compared with only 13% of the control subjects with no renal impairment [68]. Similar data were found in our own experience: a cross-sectional, unicentric study that enrolled 110 stable CKD patients not on renal replacement therapy, and 34 age- and gender-matched patients without CKD showed higher prevalence of coronary artery disease (defined as past myocardial infarction, angor pectoris associated with electrocardiographic or ultrasound indices, coronary angioplasty or bypass) in CKD (49% vs. 19%, p = 0.001). In addition, more CKD patients than Controls had valvular (38% vs. 17%, p = 0.02), and vascular calcification (carotid plaques 60% vs. 29%, p = 0.02 and abdominal aorta calcifications 54% vs. 26%, p = 0.003), irrespective of the CKD stage [69].
4.1. Arterial stiffness
Clinical consequences of vascular calcifications in CKD include loss of arterial elasticity with resultant rise in arterial stiffness due to reduced compliance of large arteries, lower delivery of oxygen to the tissues, and endothelial dysfunction. Arterial stiffness represents the functional disturbance of vascular calcification and predominantly results from greater medial calcification. The main consequence of arterial stiffness is increased pulse pressure, which contributes to left ventricular hypertrophy and impaired coronary perfusion by increasing ventricular afterload and reducing coronary blood flow during diastole [70]. In response to higher pressure or flow, the arterial wall undergoes a remodeling process, which consists of either reorganization of cellular and noncellular elements (eutrophic remodeling) or increased muscle mass (hypertrophic remodeling), both with significant impact on altered arterial function, that is, the reduced ability to buffer pressure, and pulsatile flow oscillations [71].
Aortic pulse wave velocity, an accurate and reproducible parameter of arterial stiffness and a marker of cardiovascular dysfunction, is linked to several other CV risk factors such as microalbuminuria and proteinuria, vascular calcifications, and left ventricular hypertrophy [72]. Wang and coworkers, in a study on 102 non-dialysis CKD patients, found an inverse relation between pulse wave velocity and estimated glomerular filtration rate, with a significant stepwise increase in pulse wave corresponding to the advance in CKD from stage 1 to 5 [73], suggesting that arterial stiffness increases with decreased kidney function. Contrary to this result, but in line with others which did not detect independent associations between eGFR and aortic stiffness [74, 75], in a cross-sectional, single-center study on 135 stable patients (79% with CKD), we found increased cardio-ankle vascular index (CAVI, a stiffness marker less influenced by blood pressure than pulse wave velocity) in 73% subjects, irrespective of chronic kidney disease presence and severity [76].
It is largely accepted that arterial stiffness is a powerful independent predictor of mortality and CVD in advanced CKD, as well as in general population [70].
More debatable is the influence of arterial stiffness on kidney function. In theory, besides the effects on myocardium, the decreased compliance of the large arteries would be followed by the transmission of cyclic blood flow from the aorta to peripheral microcirculations in various organs (including the kidneys) because its transformation in the physiological continuous capillary flow fails. Consequently, the protective autoregulatory mechanisms of the glomerular microcirculation are overpassed, and renal tissue becomes more vulnerable to the high blood pressure–related damage, favoring the decline in glomerular filtration [71]. Despite these pathogenetic explanations, clinical studies yielded conflicting results, as mentioned earlier. The majority of large population-based studies (adult or elderly cohorts) seem to support an independent association of aortic stiffness (measured by carotid-femoral pulse wave velocity) with the risk of incident CKD, but not with the risk of CKD progression (even if, the latter is not a unanimously reported result) [71].
The presence of arterial stiffness in CKD patients is important also from the therapeutic point of view, since numerous trials investigating the efficacy of anti-hypertensive drugs in cardiologic cohorts showed significant differences among various therapeutic regimens with regard to central hemodynamic parameters. Thus, it was found that calcium channel blockers but not beta-blockers, lower the central pulse pressure [77], so the presence of arterial stiffness could impact the choice of blood-pressure-lowering medication in CKD patients.
4.2. Atherosclerotic cardiovascular disease
Atherosclerotic lesions, which refer to intimal deposition of material with consecutive occlusive consequences, are highly prevalent in CKD patients mainly due to traditional CV risk factors. Specific features of atherosclerosis in chronic kidney disease comprise a higher proportion of calcified plaques among atherosclerotic plaques and a greater intervention of inflammatory stimuli than in general population [71]. Atherosclerosis represents one link between serum calcium and CVD with the content of coronary artery calcium emerging as a predictor of coronary heart disease [78]. Indeed, Budoff et al. showed a graded relationship between decreased kidney function in CKD patients and higher coronary artery calcification scores [79], connecting calcium and kidney function with the development of cardiovascular disease, in particular ischemic heart disease.
Even in the general population, lower level of kidney function was associated with increased 5-year probability of atherosclerotic cardiovascular disease [80]. Many studies found an inverse association between the glomerular filtration rate and the risk of occurrence or progression of atherosclerosis. For example, a cross-sectional retrospective study on almost 450 subjects with moderate to severe CKD (eGFR below 60 mL/min) and acute coronary syndrome suggested that estimated kidney function is an independent risk factor for atherosclerotic multivessel cardiovascular disease, as the decreased eGFR independently predicted a three-vessel coronary stenosis, with a magnitude dependent on the severity of renal impairment. The risk was seven times higher in patients with CKD stages 4–5 than in those with stage 1 CKD [81].
However, it should be mentioned that a significant proportion of cardiovascular death among CKD patients is not strictly related to atherosclerosis (i.e., it is not due to myocardial infarction, stroke, and heart failure), as the main event is sudden cardiac death which has a multifactorial causation [82].
Atherosclerotic lesions are usually accompanied by impairment of the endothelium. Endothelial function is often abnormal in CKD patients, who have diminished endothelium-dependent dilatation compared with controls and increased von Willebrand factor, regardless of the stage of renal disease and coexisting risk factors, suggesting that atherosclerosis may develop early in the progression of chronic kidney disease [83]. Besides common factors like age, hypertension, diabetes, smoking, dyslipidemia, and atherosclerosis, endothelial dysfunction is also accounted for by retention of uremic toxins, fluid overload, anemia, phosphate load, increased FGF23, increased homocysteine, enhanced oxidative stress, impaired nitric oxide metabolism (accumulation of asymmetrical dimethyl l-arginine), accumulation of advanced glycation end products, proinflammatory cytokines, and impaired angiogenesis [84].
Vascular calcifications of the large arteries, like abdominal aorta (assessed by the lumbar aortic calcification score—ACS) is not only a predictor of the cardiovascular morbidity and mortality, but it could also provide an indirect estimation of the intrarenal vascular status, as we found in a cross-sectional study that enrolled 77 stages 2–5 non-dialysis CKD patients, older than 50 years, and with known atherosclerotic disease. This study described increased aortic calcification as eGFR declines and found that higher lumbar aortic calcification score was independently associated with lower ankle-brachial index and higher intima-media thickness, suggesting a relationship of abdominal calcifications with the extension of atherosclerosis in other territories [85]. In addition, the novel finding of the study was the ability of an aortic calcification score >5 to predict with 65% sensitivity and 68% specificity a pathologic (<0.7) renal resistive index (marker of intrarenal atherosclerotic lesions on Doppler ultrasound) [85].
4.3. Calcific uremic arteriolopathy
Previously referred to as calciphylaxis, this is another form of vascular calcification almost exclusive to chronic kidney disease patients with kidney failure, although some cases were scarcely reported in non-CKD patients. Female gender, hyperphosphatemia, high alkaline phosphatase, and low serum albumin are among the risk factors of calcific uremic arteriolopathy [86]. It is typically found in end-stage kidney disease, obese, diabetic females, often associated with secondary hyperparathyroidism, hypercalcemia, hyperphosphatemia, malnutrition, chronic warfarin therapy, or hypercoagulability [87].
Calcific uremic arteriolopathy involves diffuse medial calcification of small- to medium-sized subcutaneous arteries and arterioles of up to 50-μm diameter, with intimal fibroproliferative occlusions that lead to necrosis. Histological abnormalities include intimal hyperplasia, inflammation, obliterative endovascular fibrosis, arteriolar medial calcification, and thrombotic cutaneous ischemia. The result is dermal, subdermal, and adipose tissue necrosis with subsequent skin ulceration. Calciphylaxis occurs independent of osteogenic activity, when the physiological calcium phosphate solubility threshold exceeds 60 mg2/dL2 [13, 86].
Overt clinical signs include livedo reticularis advancing to patches of ischemic necrosis and painful skin ulcers, especially on the legs, thighs, abdomen, or breasts. Often, the initial presenting complaint is a dull deep dermal pain with periods of neuritic-type dysesthesia associated with palpable subcutaneous nodules or dermal plaques, which evolve to livedo reticularis and then nonhealing ulcerations [7, 88]. These lesions predispose the patients to life-threatening skin necrosis or acral gangrene susceptible to supra-infectious complications. Dermal fat, lung, and mesentery are most commonly affected [7, 86].
Sepsis, which is also the main cause of death due to calcific uremic arteriolopathy, and amputation are among the severe morbidities associated with this obliterative disease.
5. Conclusions
In chronic kidney disease, even in non-dialysis stages, the prevalence of atherosclerotic lesions, vascular calcifications, and arterial stiffness are significantly higher as compared to patients of same-age without kidney damage. Because the interplay of multiple factors is responsible for the arterial disorders in CKD, the exact mechanism involved is still a matter of debate. Therefore, the best therapeutic approach to minimize the adverse impact of CKD-related mineral and bone disorder on the patients’ outcome is not yet known and controversies exist especially regarding the influence of intestinal phosphate binders and vitamin D receptor activators on arterial calcifications.
\n',keywords:"atherosclerosis and arteriosclerosis, arterial stiffness, calcifications, cardiovascular morbidity, chronic kidney disease",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/58465.pdf",chapterXML:"https://mts.intechopen.com/source/xml/58465.xml",downloadPdfUrl:"/chapter/pdf-download/58465",previewPdfUrl:"/chapter/pdf-preview/58465",totalDownloads:1353,totalViews:238,totalCrossrefCites:1,totalDimensionsCites:2,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:63,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"August 18th 2017",dateReviewed:"November 24th 2017",datePrePublished:"December 20th 2017",datePublished:"February 21st 2018",dateFinished:"December 27th 2017",readingETA:"0",abstract:"Chronic kidney disease (CKD), a major public health problem that affects up to 10–13% of the general population worldwide, imposes considerable socio-economic burden due to both the need for renal replacement therapy and, even more important, the negative influence on the overall patients’ health status. Cardiovascular (CV) diseases are the main cause of death in CKD patients and are triggered not only by the traditional CV risk factors but also by specific, uremia-related, factors. Among these, calcium-phosphate and bone metabolism disorders play a central role. Abnormalities of mineral metabolism occur early, evolve silently as the kidney function deteriorates, and are associated with CV morbidity and mortality, mainly by the development of valvular and vascular calcifications. This chapter aims to summarize the recent knowledge on the types and mechanisms of arterial calcifications, as well as their clinical implications, in the setting of CKD. The issue is significant for both nephrologists and cardiologists and could be an example of the requirement for interdisciplinary collaboration in the medical practice.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/58465",risUrl:"/chapter/ris/58465",book:{id:"5955",slug:"chronic-kidney-disease-from-pathophysiology-to-clinical-improvements"},signatures:"Cristina Capusa and Daria Popescu",authors:[{id:"220208",title:"Associate Prof.",name:"Cristina",middleName:null,surname:"Capusa",fullName:"Cristina Capusa",slug:"cristina-capusa",email:"ccalexandr@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"225929",title:"Dr.",name:"Daria",middleName:null,surname:"Popescu",fullName:"Daria Popescu",slug:"daria-popescu",email:"dariampopescu@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Types and characteristics of vascular calcification in chronic kidney disease",level:"1"},{id:"sec_3",title:"3. Pathogenesis of vascular calcifications in chronic kidney disease",level:"1"},{id:"sec_3_2",title:"3.1. Overview on the molecular basis of mineralization and vascular calcifications",level:"2"},{id:"sec_4_2",title:"3.2. How does chronic kidney disease favor vascular calcifications?",level:"2"},{id:"sec_4_3",title:"3.2.1. Imbalance between pro- and counter-calcification factors",level:"3"},{id:"sec_5_3",title:"3.2.2. Mineral metabolism abnormalities and vascular calcifications",level:"3"},{id:"sec_8",title:"4. Clinical consequences of vascular calcifications in chronic kidney disease",level:"1"},{id:"sec_8_2",title:"4.1. Arterial stiffness",level:"2"},{id:"sec_9_2",title:"4.2. Atherosclerotic cardiovascular disease",level:"2"},{id:"sec_10_2",title:"4.3. Calcific uremic arteriolopathy",level:"2"},{id:"sec_12",title:"5. 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DOI: 10.1111/j.1365-2362.2010.02271.x'},{id:"B38",body:'Parker BD, Ix JH, Cranenburg ECM, Vermeer C, Whooley MA, Schurgers LJ. Association of kidney function and uncarboxylated matrix Gla protein: Data from the Heart and Soul Study. Nephrology, Dialysis, Transplantation. 2009;24(7):2095-2101. DOI: 10.1093/ndt/gfp024'},{id:"B39",body:'Montezano AC, Zimmerman D, Yusuf H, Burger D, Chignalia AZ, Wadhera V, van Leeuwen FN, Touyz RM. Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium. Hypertension. 2010;56:453-462. DOI: 10.1161/HYPERTENSIONAHA.110.152058'},{id:"B40",body:'Molostvov G, James S, Fletcher S, Bennett J, Lehnert H, Bland R, Zehnder D. Extracellular calcium-sensing receptor is functionally expressed in human artery. American Journal of Physiology. Renal Physiology. 2007;293(3):F946-F955. DOI: 10.1152/ajprenal.00474.2006'},{id:"B41",body:'Giachelli CM. The emerging role of phosphate in vascular calcification. 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The New England Journal of Medicine. 2012;367:2482-2494. DOI: 10.1056/NEJMoa1205624'},{id:"B60",body:'Schlieper G, Schurgers L, Brandenburg V, Reutelingsperger C, Floege J. Vascular calcification in chronic kidney disease: An update. Nephrology, Dialysis, Transplantation. 2016;31(1):31-39. DOI: 10.1093/ndt/gfv111'},{id:"B61",body:'Nakayama M, Kaizu Y, Nagata M, Ura Y, Ikeda H, Shimamoto S, Kuma K. Fibroblast growth factor 23 is associated with carotid artery calcification in chronic kidney disease patients not undergoing dialysis: A cross-sectional study. BMC Nephrology. 2013;14:22. DOI: 10.1186/1471-2369-14-22'},{id:"B62",body:'Lee YT, Ng HY, Chiu TTY, Li LC, Pei SN, Kuo WH, Lee CT. Association of bone-derived biomarkers with vascular calcification in chronic hemodialysis patients. Clinica Chimica Acta. 2016;452:38-43. DOI: 10.1016/j.cca.2015.10.031'},{id:"B63",body:'Scialla JJ, Lau WL, Reilly MP, Isakova T, Yang HY, Crouthamel MH, Chavkin NW, Rahman M, Wahl P, Amaral AP, Hamano T, Master SR, Nessel L, Chai B, Xie D, Kallem RR, Chen J, Lash JP, Kusek JW, Budoff MJ, Giachelli CM, Wolf M, for Chronic Renal Insufficiency Cohort Study Investigators. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney International. 2013;83(6):1159-1168. DOI: 10.1038/ki.2013.3'},{id:"B64",body:'Yamada S, Giachelli CM. Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho. Bone. 2017;100:87-93. DOI: 10.1016/j.bone.2016.11.012'},{id:"B65",body:'MC H, Shi M, Zhang J, Quiñones H, Griffith C, Kuro-o M, Moe OW. Klotho deficiency causes vascular calcification in chronic kidney disease. Journal of the American Society of Nephrology. 2011;22(1):124-136. DOI: 10.1681/ASN.2009121311'},{id:"B66",body:'United States Renal Data System. 2014 USRDS annual data report: Epidemiology of kidney disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2014. Available from https://www.usrds.org/2014/download/V1_Ch_04_Cardiovascular-Disease_14.pdf [Accessed 2017.10.08]'},{id:"B67",body:'Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. The New England Journal of Medicine. 2004;351:1296-1305. DOI: 10.1056/NEJMoa041031'},{id:"B68",body:'Russo D, Palmiero G, De Blasio AP, Balletta MM, Andreucci VE. Coronary artery calcification in patients with CRF not undergoing dialysis. American Journal of Kidney Diseases. 2004;44(6):1024-1030. DOI: 10.1053/j.ajkd.2004.07.022'},{id:"B69",body:'Badulescu M, Capusa C, Stancu S, Blaga V, Ilyes A, Anghel C, Mircescu G. Cardiovascular abnormalities prevalence in non-dialysis chronic kidney disease patients. In: Abstracts to the XLVIIIth ERA-EDTA Congress, Praga, 23-26 June 2011. NDT Plus. 2011;4(suppl 2):4.s2.48. DOI: 10.1093/ndtplus/4.s2.48'},{id:"B70",body:'Toussaint ND, Kerr PG. Vascular calcification and arterial stiffness in chronic kidney disease: Implications and management. Nephrology (Carlton). 2007;12(5):500-509. DOI: 10.1111/j.1440-1797.2007.00823.x'},{id:"B71",body:'Garnier AS, Briet M. Arterial stiffness and chronic kidney disease. Pulse. 2015;3:229-241. DOI: 10.1159/000443616'},{id:"B72",body:'Bellasi A, Ferramosca E, Ratti C. Arterial stiffness in chronic kidney disease: The usefulness of a marker of vascular damage. International Journal of Nephrology. 2011;2011:734832. DOI: 10.4061/2011/734832'},{id:"B73",body:'Wang MC, Tsai WC, Chen JY, Huang JJ. Stepwise increase in arterial stiffness corresponding with the stages of chronic kidney disease. American Journal of Kidney Diseases. 2005;45(3):2044-2053. DOI: 10.1053/j.ajkd.2004.11.011'},{id:"B74",body:'Briet M, Bozec E, Laurent S, Fassot C, London GM, Jacquot C, Froissart M, Houillier P, Boutouyrie P. Arterial stiffness and enlargement in mild-to-moderate chronic kidney disease. Kidney International. 2006;69:350-357. DOI: 10.1038/sj.ki.5000047'},{id:"B75",body:'Hermans MM, Henry R, Dekker JM, Kooman JP, Kostense PJ, Nijpels G, Heine RJ, Stehouwer CD. Estimated glomerular filtration rate and urinary albumin excretion are independently associated with greater arterial stiffness: The Hoorn Study. Journal of the American Society of Nephrology. 2007;18:1942-1952. DOI: 10.1681/ASN.2006111217'},{id:"B76",body:'Capusa C, Boitan B, Stefan G, Barsan L, Blaga V, Mircescu G. Age and malnutrition markers are predictors of arterial stiffness in adults with and without chronic kidney disease. In: Abstracts to the LIIth ERA-EDTA Congress, London, 28-31 May 2015. Nephrology Dialysis Transplantation. 2015;30(suppl 3):iii491. DOI: 10.3252/pso.eu.52era.2015'},{id:"B77",body:'Dudenbostel T, Glasser SP. Effects of antihypertensive drugs on arterial stiffness. Cardiology in Review. 2012;20(5):259-263. DOI: 10.1097/CRD.0b013e31825d0a44'},{id:"B78",body:'Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, Liu K, Shea S, Szklo M, Bluemke DA, O\'Leary DH, Tracy R, Watson K, Wong ND, Kronmal RA. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. The New England Journal of Medicine. 2008;358(13):1336-1345. DOI: 10.1056/NEJMoa072100'},{id:"B79",body:'Budoff MJ, Rader DJ, Reilly MP, Mohler ER 3rd, Lash J, Yang W, Rosen L, Glenn M, Teal V, Feldman HI, for CRIC Study Investigators. Relationship of estimated GFR and coronary artery calcification in the CRIC (Chronic Renal Insufficiency Cohort) study. American Journal of Kidney Diseases. 2011;58(4):519-526. DOI: 10.1053/j.ajkd.2011.04.024'},{id:"B80",body:'Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, Coresh J, Levey AS, Sarnak MJ. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. Journal of the American College of Cardiology. 2003;41(1):47-55. DOI: 10.1016/S0735-1097(02)02663-3'},{id:"B81",body:'Olechnowicz-Tietz S, Gluba A, Paradowska A, Banach M, Rysz J. The risk of atherosclerosis in patients with chronic kidney disease. International Urology and Nephrology. 2013;45(6):1605-1612. DOI: 10.1007/s11255-013-0407-1'},{id:"B82",body:'Whitman IR, Feldman HI, Deo R. CKD and sudden cardiac death: Epidemiology, mechanisms, and therapeutic approaches. Journal of the American Society of Nephrology. 2012;23(12):1929-1939. DOI: 10.1681/ASN.2012010037'},{id:"B83",body:'Thambyrajaha J, Landraya MJ, McGlynnb FJ, Jonesa HJ, Wheelerb DC, Townenda JN. Abnormalities of endothelial function in patients with predialysis renal failure. Heart. 2000;83:205-209. DOI: 10.1136/heart.83.2.205'},{id:"B84",body:'Goligorsky MS. Pathogenesis of endothelial cell dysfunction in chronic kidney disease: A retrospective and what the future may hold. Kidney Research and Clinical Practice. 2015;34(2):76-82. DOI: 10.1016/j.krcp.2015.05.003'},{id:"B85",body:'Stefan G, Capusa C, Stancu S, Petrescu L, Nedelcu ED, Andreiana I, Mircescu G. Abdominal aortic calcification and renal resistive index in patients with chronic kidney disease: Is there a connection? Journal of Nephrology. 2014;27(2):173-179. DOI: 10.1007/s40620-013-0021-4'},{id:"B86",body:'Disthabanchong S. Vascular calcification in chronic kidney disease: Pathogenesis and clinical implication. World Journal of Nephrology. 2012;1(2):43-53. DOI: 10.5527/wjn.v1.i2.43'},{id:"B87",body:'Schiffrin EL, Lipman M, Mann JFE. Chronic kidney disease: Effects on the cardiovascular system. 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“Carol Davila” University of Medicine and Pharmacy, Romania
“Dr. Carol Davila” Teaching Hospital of Nephrology, Romania
“Carol Davila” University of Medicine and Pharmacy, Romania
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1. Introduction
Hypoxia is critical for the life. Autonomic nerves system responds to the hypoxia regulating circulatory and respiratory organs to ensure adequate oxygen delivery. Separately, cellular responses to hypoxia are mainly regulated by the activation of transcription factors called hypoxia-inducible factors (HIFs). HIFs affect hypoxia and stress response signaling pathways that influence development, metabolism, inflammation, and circulatory and respiratory physiology [1, 2, 3, 4, 5]. Hypoxia-inducible factors are also associated with many diseases in the circulatory system, mainly via VEGF. Copper is a co-factor of bFGF, accumulated in malignant glioma, the chelation inhibits glioma growth and angiogenesis in murine model. HIF pathways are triggered by hypoxia. The hypoxia regulates both in the cell signal level and in the circulatory and respiratory system by autonomic nerves. Hence, compromised response to ischemia is crucial. Inhibition of angiogenesis by reducing the HIF pathway can be a rational method in patients with ischemic diseases. Investigation regarding hypoxia mediated by intracellular signaling have been emerged as new targets focusing on the related genes or protein delivery to stabilize HIFs, but not yet accomplished. Oxygen tension is markedly below physiological levels in solid tumors also in pituitary adenoma. In fact, solid tumors contain severely hypoxic regions, in which pO2 values are <10 mmHg [6, 7]. Tumor vessels raised by VEGF are regularly lacking tight junction, we consider that it leads pituitary apoplexy, hemorrhagic infarction.
In this chapter, we focus on the current understanding of the relationship between HIFs and pituitary adenoma in tumor angiogenesis.
2. Discussion
Endocan is known as endothelial cell-specific molecule-1 (ESM-1) that has a 50 kDa polypeptide with a single dermatan sulfate [8, 9]. After secreted from endothelial cell, endocan interacts between leukocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1). Recent studies have shown that endocan mRNA expression in endothelial cells is specific to several angiogenic factors and cytokine, such as VEGF and TNF. Herein, function of endocan has been emerged in tumor hypoxia context. Endocan overexpress stimulates tumor progression in mouse models of human tumor xenografts. Anyway, these studies demonstrated that endocan can be a biomarker of tumor progression, and a potentially therapeutic target for cancer. Despite general immunotherapeutic therapy to cancer is not satisfactory, antibodies against endocan be still promising cancer treatment. Both plasma endocan and VEGF-A levels are elevated in patients with invasive tumor. Cornellius showed that, pituitary adenoma cells expressed endocan, though it was not observed in all normal pituitary [10]. Microvessels revealed significantly greater mean vessel areas in subgroups of tumors with endothelial endocan expression. Thus, endocan in endothelial cells may be a relevant marker of aggressiveness in pituitary tumors.
Two p53 binding sites are present in the promoter sequence of the gene encoding cathepsin D [11, 12] suggesting a direct relationship between cathepsin D and the induction of apoptosis. Cathepsin D is activated by an intracellular acid-dependent autoactivation mechanism. It has been reported that cathepsin D secreted by prostate carcinoma cells is responsible for the generation of angiostatin, an endogenous inhibitor of angiogenesis that is produced by the tumor-mediated proteolysis of plasminogen. Clinically, cathepsin D overexpression has been studied in several malignant tumor types [11] although most research has been focused on breast cancer, in which cathepsin D expression correlates with poor prognosis. Expression of cathepsin D is also significantly higher in malignant than in benign ovarian tumors [12]. In colon cancer cells, cathepsin D is upregulated by HIF 1α under hypoxic conditions, perhaps counteracting the effects of VEGF via angiostatin regulation [13]. Angiogenesis is a major mechanism by which oxygen supply is increased in tumors. Hypoxia has been found to regulate angiogenesis activators and may some- times downregulate angiogenesis inhibitors. In the mouse pituitary adenoma cell line GH4C, secretion of cathepsin D was inhibited under hypoxic conditions, suggesting that hypoxia acts directly on pituitary lactotrophs to inhibit PRL expression. In addition, cathepsin D can promote tumor invasiveness by acting as an autocrine growth factor within the pituitary to stimulate cell growth. The hormonal moiety in the hypoxia-responsive motif, however, has not yet been established.
In pituitary adenomas, regional oxygen saturation is lower than in normal pituitary lobes. VEGF and HIF-1α are also expressed in several pituitary adenomas; however, the role of HIF-1α and the relationship between HIF-1α and VEGF has been emerged Vidal et al. reported that HIF-1α was expressed in all types of pituitary adenoma and that the expression level in GH-producing pituitary adenomas and pituitary carcinomas was higher than in the other adenomas. We detected HIF-1α mRNA and protein in several pituitary adenoma types. Our statistical analysis confirmed earlier results that there was no significant correlation between HIF-1α expression and patient age, gender, and tumor size. GH-producing adenomas exhibited the highest, and ACTH-producing adenomas the lowest expression levels of HIF-1α; however, the difference was not statistically significant, possibly due to the small number of available samples. Our study confirmed earlier reports that VEGF was expressed in all types of pituitary adenoma [14, 15]. According to Lloyd et al., VEGF expression was high in GH-producing adenomas, corticotrophs, silent corticotrophs, silent subtype 3 tumors, non-oncocytic null-cell adenomas, and pituitary carcinomas [16]. However, between normal tissue and adenomas or tumors of different histotypes, there was no statistically significant difference with respect to VEGF expression. We also found no significant difference among the different adenoma types we examined.
We performed quantitative assessment of the expression of HIF-1α and VEGF in pituitary adenomas and examined the co-expression of HIF-1α and VEGF. Our results suggest that VEGF may be regulated not only by HIF-1α but by a different mechanism mediated by several cytokines and growth factors. In normal pituitary cells, pituitary adenylate cyclase-activating polypeptide (PACAP) and IL-6 can stimulate VEGF expression in vitro, whereas glucocorticoid has inhibitory action. In pituitary adenoma cells, VEGF expression was increased by TGF-α, PACAP, estradiol, IL-6, IGF-I, and pituitary tumor transforming gene (PTTG), and was inhibited by dexamethasone. Moreover, VEGF was co-localized with various pituitary hormones, suggesting that hypothalamic factors may play a role in the regulation of pituitary VEGF release. Therefore, the regulation of VEGF in pituitary tumors may not depend primarily on HIF-1α expression.
Our study also demonstrated that stromal cell-derived factor (SDF)-1 expression was positively correlated to microvascular density (MVD), strongly obvious in macroadenomas. Intensity for immunoreactivity for SDF-1 was not related. Given by these results we consider, abnormal blood vessels in the pituitary adenoma tissue may be not be able to supply the normal oxygen concentration like the normal vessels. Both SDF-1 mRNA and protein expression were firmly upregulated in hypoxia, and then regulate tumor angiogenesis in pituitary adenoma.
SDF-1 (CXCL12) is expressed both in embryo and cancer cell lines, and is an ELR-CXC chemokine that has angiogenic activity, role of the capillary-like formation stimulating human vascular endothelial cells also in pituitary adenoma [17]. Meanwhile CD34 is a cell-surface marker of hematopoietic stem cells (HSCs), mature vascular endothelial cells also express a receptor for SDF-1, CXCR4. CD34 cell migration is stimulate by CXCR4 via SDF-1 in vitro and could be a key factor for trafficking HSC between the peripheral blood and the bone marrow, named a homing effect. During embryogenesis, primitive blood vessels are shaped newly by the angioblasts aggregation, which is termed vasculogenesis.
In embryo, when the vasculogenesis starts mainly fibroblast growth factors (FGFs) cause some cells in the mesoderm differentiated into endothelial progenitors. SDF-1/CXCR4 axis has an initial role in all of hematopoiesis, vascular development, and cardiogenesis [18, 19, 20], whiles also in adults, homing of HSCs to the bone marrow and CD34 progenitor cell proliferation is regulated by SDF-1 [17]. Various organs, such as the liver, brain, and lymphoid organs widely expressed SDF-1. In particular, human ovarian cancer was firstly discuss to express high levels of SDF-1, and subsequently has been reported in glioblastoma.
Recently, several studies have focused on pituitary adenoma. Some showed that SDF-1 and its receptor, CXCR4, were expressed in rat pituitary adenomas, but they did not discuss the relationship between SDF-1 expression and angiogenesis [21, 22, 23]. Both prolactin and GH in the GH4C1 are regulated in cell proliferation and the release by CXCR4 activation, plausibly through complicated intracellular signals. However, discussion of exogenous SDF-1 has not yet clearly disclosed, because pituitary adenoma cells express CXCR4 but not SDF-1. Barbieri et al. analyzed the expression of both SDF-1 and CXCR4 in human pituitary adenomas, compared with normal hypophyses. They elucidated first the SDF-1 and CXCR4 expression in normal and adenomatous human pituitary and revealed that overexpression occurs in adenomas comparing normal-related pituitary cells, then indicating that this profile may contribute to the increasing proliferation [24].
Invasive pituitary adenoma has a complicated mechanism and interacts with the nerve-endocrine-immune network. It is affect DDR1 ligand combined with DDR1 can promote the DDR1 signaling pathway. DDR1 promotes MMP-2/9 expression, leading to ECM reconstruction and tumor invasion [25, 26, 27]. Cell apoptosis, change tumor cell invasiveness, and regulation of energy metabolism is mediated by hypoxic condition. Herein, discoidin domain receptor (DDR)-1 expression and its effect on pituitary adenoma under hypoxia still need further investigation. Our study confirmed that DDR1 mRNA and protein are elevated in primary pituitary adenoma cells along with hypoxia. Elevated DDR1 expression can regulated expression of MMP-2 and MMP-9 expression in supernatant, thereby promoting cell proliferation and invasion of pituitary adenoma. Nilotinib administration can diminish DDR1 expression and further reduce MMP-2 and -9 expression to reduce pituitary adenoma cells proliferation and invasion.
The above-mentioned factors have been discussed much few in pituitary adenoma. Cornelius et al. investigated that endocan, secreted by endothelial cells, associated with an aggressive behavior in pituitary tumors. The study by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) in patients operated for a pituitary adenoma, comparing normal post-mortem pituitaries. In normal pituitaries, endocan was never observed in vessels but was detectable in adenoma cells. In adenoma tissue, a significant relation between endocan immunoreactivity in endothelial cells and progression, tumor size, mitotic count, and p53 expression were demonstrated. The immunohistological study of endocan in endothelial cells therefore can be a new marker of aggressive behavior in pituitary tumors [28].
Cathepsin B expressed in invasive pituitary adenoma and is an important functional protein in apoptosis. One might hypothesize that shifting the balance between mediators of cell death could result in changes in pituitary tumor behavior [29].
Pituitary adenoma is considered to be benign, accounting 20% of intracranial tumors generally, that is the third most common intracranial tumor. But approximately 30% of pituitary adenomas are invasive. It can be said the already-established molecular mechanisms of the pituitary adenomas invasion, turning out mainly HIF-1α, pituitary tumor transforming gene, FGF-2, VEGF, and MMPs (mainly MMP-2, and MMP-9) are core signaling. These molecules have the ability to create a suitable microenvironment within the tumor. Together, they have a complicated interaction [30].
Nonfunctioning pituitary adenoma is sometime hard for surgery. However, there is no established conservative treatment. MicroRNA-134 (miR-134) may be promised that suppress tumor cell proliferation and invasion. Therefore, the effect of miR-134 on improving non-functioning pituitary tumor cells expansion is considered to be challenging. The molecular mechanism of the SDF-1α/miR-134/VEGFA axis is representative a novel mechanism in the pathogenesis of NF-PitNETs and may serve as a potential therapeutic target for the treatment of NF-PitNETs [31].
Study with flow cytometry show that the rates of CXCR4- and CXCL12-positive cells in invasive pituitary adenomas was significantly elevated in the cell suspensions than those in non-invasive pituitary adenomas. Immunohistochemical study unveiled that CXCR4 and CXCL12 staining index of the invasive pituitary adenomas were clearly higher than those of the non-invasive pituitary adenomas. Meanwhile, none of flow cytometry and immunohistochemistry could disclose significant difference between CD44 and CD147 expression, respectively. Then, CXCR4 and CXCL12 may potentially can be powerful biomarkers to detect early stage of pituitary adenomas [32].
Recently, Nilotinib has been highlighted to reduce DDR1 expression, decrease MMP-2 and MMP-9 expression, and inhibit pituitary adenoma cells proliferation and invasion [33].
Conclusively further investigations are required to elucidate the mechanisms underlying the invasiveness of pituitary adenoma-related phenomena is a new horizon in the field of neuro-oncology.
Conflict of interest
The authors declare no conflicts of interest.
\n',keywords:"hypoxia inducible factors, tumor angiogenesis, pituitary adenoma",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80121.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80121.xml",downloadPdfUrl:"/chapter/pdf-download/80121",previewPdfUrl:"/chapter/pdf-preview/80121",totalDownloads:63,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 22nd 2021",dateReviewed:"December 23rd 2021",datePrePublished:"January 20th 2022",datePublished:null,dateFinished:"January 19th 2022",readingETA:"0",abstract:"The role of angiogenesis in pituitary tumor development used to be questioned, since pituitary tumors have been usually found to be less vascularized than the normal pituitary tissue. Nevertheless, a significantly higher degree of vasculature has been shown in invasive or macropituitary prolactinomas when compared to noninvasive and microprolactinomas. We should know VEGF was found firstly in pituitary anterior lobe, then tumor angiogenesis must occur. Meanwhile the vascular arrangement raised by VEGF is irregular, that sometimes lead to pituitary apoplexy. In this chapter, hypoxia inducible factors (HIF), transcription factors regulating expression of several genes related to oxygen homeostasis are in response to hypoxic stress. We focus on tumor angiogenesis regulated by the signaling cascade in tumor angiogenesis in pituitary tumor.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80121",risUrl:"/chapter/ris/80121",signatures:"Daizo Yoshida and Akira Teramoto",book:{id:"10833",type:"book",title:"Tumor Angiogenesis",subtitle:null,fullTitle:"Tumor Angiogenesis",slug:null,publishedDate:null,bookSignature:"Dr. Ke Xu",coverURL:"https://cdn.intechopen.com/books/images_new/10833.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-835-6",printIsbn:"978-1-80355-834-9",pdfIsbn:"978-1-80355-836-3",isAvailableForWebshopOrdering:!0,editors:[{id:"59529",title:"Dr.",name:"Ke",middleName:null,surname:"Xu",slug:"ke-xu",fullName:"Ke Xu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Discussion",level:"1"},{id:"sec_6",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Molecular Pharmacology. 2006;70(5):1469-1480'},{id:"B2",body:'Fallah J, Rini BI. HIF inhibitors: Status of current clinical development. Current Oncology Reports. Jan 22 2019;21(1):6'},{id:"B3",body:'Albadari N, Deng S, Li W. The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. Expert Opinion on Drug Discovery. Jul 2019;14(7):667-682'},{id:"B4",body:'Graham K, Unger E. Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment. International Journal of Nanomedicine. Oct 2018;13:6049-6058'},{id:"B5",body:'Hsu TS, Lin YL, Wang YA, Mo ST, Chi PY, Lai AC, et al. HIF-2α is indispensable for regulatory T cell function. Nature Communications. Oct 6 2020;11(1):5005. doi: 10.1038/s41467-020-18731-y'},{id:"B6",body:'Bhandari V, Hoey C, Liu LY, Lalonde E, Ray J, Livingstone J, et al. Molecular landmarks of tumor hypoxia across cancer types. Nature Genetics. Feb 2019;51(2):308-318'},{id:"B7",body:'De Freitas Caires N, Gaudet A, Portier L, Tsicopoulos A, Mathieu D, Lassalle P. Endocan, sepsis, pneumonia, and acute respiratory distress syndrome. Critical Care. Oct 26 2018;22(1):280'},{id:"B8",body:'Kuluöztürk M, İn E, İlhan N. Endocan as a marker of disease severity in pulmonary thromboembolism. The Clinical Respiratory Journal. Dec 2019;13(12):773-780'},{id:"B9",body:'Cornelius A, Cortet-Rudelli C, Assaker R, Kerdraon O, Gevaert M-H, Prévot V, et al. Endothelial expression of endocan is strongly associated with tumor progression in pituitary adenoma. Brain Pathology. 2012;22(6):757-764'},{id:"B10",body:'Minarowska A, Gacko M, Karwowska A, Minarowski Ł. Human cathepsin D. Folia Histochemica et Cytobiologica. 2008;46(1):23-38'},{id:"B11",body:'Kakimoto Y, Sasaki A, Niioka M, Kawabe N, Osawa M. Myocardial cathepsin D is downregulated in sudden cardiac death. PLoS One. Mar 16 2020;15(3). DOI: 10.1371/journal.pone.0230375'},{id:"B12",body:'Pranjol ZI, Whatmore JL. Cathepsin D in the tumor microenvironment of breast and ovarian cancers. Advances in Experimental Medicine and Biology. 2020;1259:1-16'},{id:"B13",body:'Basu S, Cheriyamundath S, Gavert N, Brabletz T, Haase G, Ben-Ze\'ev A. Increased expression of cathepsin D is required for L1-mediated colon cancer progression. Oncotarget. Aug 27 2019;10(50):5217-5228'},{id:"B14",body:'Kim K, Yoshida D, Teramoto A. Expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor in pituitary adenomas. Endocrine Pathology. Summer 2005;16(2):115-121'},{id:"B15",body:'Yoshida D, Noha M, Watanabe K, Sugisaki Y, Teramoto A. Novel approach to analysis of in vitro tumor angiogenesis with a variable-pressure scanning electron microscope: Suppression by matrix metalloproteinase inhibitor SI-27. Tumor Pathology. 2001;18(2):89-100'},{id:"B16",body:'Vascular endothelial growth factor (VEGF) expression in human pituitary adenomas and carcinomas Ricardo V. Lloyd, Bernd W. Scheithauer, Takao Kuroki, Sergio Vidal, Kalman Kovacs, Lucia Stefaneanu Endocrine Pathology. Autumn 1999;10(3):229-235'},{id:"B17",body:'Barbieri F, Bajetto A, Porcile C, Pattarozzi A, Schettini G, Florio T. Role of stromal cell-derived factor 1 (SDF1/CXCL12) in regulating anterior pituitary function. Journal of Molecular Endocrinology. Mar 2007;38(3):383-389'},{id:"B18",body:'Barbieri F, Bajetto A, Stumm R, Pattarozzi A, Porcile C, Zona G, et al. Overexpression of stromal cell-derived factor 1 and its receptor CXCR4 induces autocrine/paracrine cell proliferation in human pituitary adenomas. Clinical Cancer Research. Aug 15 2008;14(16):5651-5672'},{id:"B19",body:'Bajetto A, Barbieri F, Dorcaratto A, Barbero S, Daga A, Porcile C, et al. Expression of CXC chemokine receptors 1-5 and their ligands in human glioma tissues: Role of CXCR4 and SDF1 in glioma cell proliferation and migration. Neurochemistry International. Oct 2006;49(5):423-432'},{id:"B20",body:'Bajetto A, Bonavia R, Barbero S, Piccioli P, Costa A, Florio T, et al. Glial and neuronal cells express functional chemokine receptor CXCR4 and its natural ligand stromal cell-derived factor 1. Journal of Neurochemistry. Dec 1999;73(6):2348-2357'},{id:"B21",body:'Li S, Zhang Z, Xue J, Guo X, Liang S, Liu A. Effect of hypoxia on DDR1 expression in pituitary adenomas. Medical Science Monitor. Aug 19 2015;21:2433-2438'},{id:"B22",body:'Yoshida D, Teramoto A. Enhancement of pituitary adenoma cell invasion and adhesion is mediated by discoidin domain receptor-1. Journal of Neuro-Oncology. Mar 2007;82(1):29-40'},{id:"B23",body:'Hilton HN, Stanford PM, Harris J, Oakes SR, Kaplan W, Daly RJ, et al. KIBRA interacts with discoidin domain receptor 1 to modulate collagen-induced signalling. Biochimica et Biophysica Acta. Mar 2008;1783(3):383-389'},{id:"B24",body:'Porcile C, Bajetto A, Barbieri F, Barbero S, Bonavia R, Biglieri M, et al. Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation. Experimental Cell Research. Aug 15 2005;308(2):241-253'},{id:"B25",body:'Yang Q, Li X. Molecular network basis of invasive pituitary adenoma: A review. Frontiers in Endocrinology. Jan 24 2019;10:7'},{id:"B26",body:'Ruskyte K, Liutkevicienė R, Vilkeviciute A, Vaitkiene P, Valiulytė I, Glebauskiene B, et al. MMP-14 and TGFbeta-1 methylation in pituitary adenomas. Oncology Letters. Oct 2016;12(4):3013-3017'},{id:"B27",body:'Gupta P, Dutta P. Landscape of molecular events in pituitary apoplexy. Frontiers in Endocrinology. Mar 20 2018;9:107'},{id:"B28",body:'Cornelius A, Cortet-Rudelli C, Assaker R, Kerdraon O, Gevaert M-H, Prévot V, et al. Endothelial expression of endocan is strongly associated with tumor progression in pituitary adenoma. Brain Pathology. 2012;22(6):757-764'},{id:"B29",body:'Tanase C, Popescu ID, Mihai S, Necula L, Cruceru ML, Hinescu ME. Decreased expression of APAF-1 and increased expression of cathepsin B in invasive pituitary adenoma. Oncotargets and Therapy. Dec 22 2014;8:81-90'},{id:"B30",body:'Yang Q, Li X. Molecular network basis of invasive pituitary adenoma: A review. Frontiers in Endocrinology. Jan 24 2019;10:7'},{id:"B31",body:'Wang X, Fang Y, Zhou Y, Guo X, Ke X, Li C, et al. SDF-1α/MicroRNA-134 axis regulates nonfunctioning pituitary neuroendocrine tumor growth via targeting VEGFA. Frontiers in Endocrinology. Dec 9 2020;11. DOI 10.3389/fendo.2020.566761'},{id:"B32",body:'Xing B, Kong YG, Yao Y, Lian W, Wang RZ, Ren ZY. Study on the expression levels of CXCR4, CXCL12, CD44, and CD147 and their potential correlation with invasive behaviors of pituitary adenomas. Biomedical and Environmental Sciences. Jul 2013;26(7):592-598'},{id:"B33",body:'Li S, Li S, Zhang Z, Xue J, Guo X, Liang S, et al. Effect of hypoxia on DDR1 expression in pituitary adenomas. Medical Science Monitor. Aug 19 2015;21:2433-2438'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Daizo Yoshida",address:"dyoshida@nms.ac.jp",affiliation:'
Department of Neurological Surgery, Nippon Medical School, Tokyo, Japan
Department of Neurological Surgery, Nippon Medical School, Tokyo, Japan
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Dr. Wang is a member of the American Society of Mechanical Engineers (ASME), Institute of Electrical and Electronics Engineers (IEEE), American Association for the Advancement of Science (AAAS), Physiological Society of New Zealand (PSNZ), and Institution of Professional Engineers New Zealand (IPENZ). Her research interests include medical devices, electromagnetic sensing and imaging, and computational mechanics. Over the past five years, Dr. Wang has authored more than seventy peer-reviewed publications, two ASME books, seven book chapters, and ten issued patents. She is an active reviewer of numerous journals, books, and conferences. She has edited four books and three special issues of international journals. She has received multiple national and international awards from various professional societies and organizations. 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Choosing to publish with IntechOpen ensures the following benefits:
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Indexing and listing across major repositories, see details ...
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Long-term archiving
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Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
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Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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Proven world leader in Open Access book publishing with over 10 years experience
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+5,700 OA books published
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Most competitive prices in the market
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Fully compliant with OA funding requirements
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Optimized processes that assure your research is made available to the scientific community without delay
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Personal support during every step of the publication process
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+184,650 citations in Web of Science databases
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Currently strongest OA platform with over 175 million downloads
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
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The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
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OAPF Publishing Options
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1,400 GBP Chapter - Edited Volume
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850 GBP Chapter - Book Series Topic (Annual Volume)
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10,000 GBP Monograph - Long Form
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4,000 GBP Compacts Monograph - Short Form
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850 GBP Journal Article (Across Portfolio)
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During the launching phase journals do not charge an APC, rather they will be funded by IntechOpen.
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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Services included are:
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An online manuscript tracking system to facilitate your work
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Assurance that your manuscript meets the highest publishing standards
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Discoverability - electronic citation and linking via DOI
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Permanent and unrestricted online access to your work
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What isn't covered by the Open Access Publishing Fee?
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If your manuscript:
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\n\t
Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
\n\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
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\n\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
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Open Access Funding
\n\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\n
Added Value of Publishing with IntechOpen
\n\n
Choosing to publish with IntechOpen ensures the following benefits:
\n\n
\n\t
Indexing and listing across major repositories, see details ...
\n\t
Long-term archiving
\n\t
Visibility on the world's strongest OA platform
\n\t
Live Performance Metrics to track readership and the impact of your chapter
\n\t
Dissemination and Promotion
\n
\n\n
Benefits of Publishing with IntechOpen
\n\n
\n\t
Proven world leader in Open Access book publishing with over 10 years experience
\n\t
+5,700 OA books published
\n\t
Most competitive prices in the market
\n\t
Fully compliant with OA funding requirements
\n\t
Optimized processes that assure your research is made available to the scientific community without delay
\n\t
Personal support during every step of the publication process
\n\t
+184,650 citations in Web of Science databases
\n\t
Currently strongest OA platform with over 175 million downloads
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Oguntibeju",authors:[{id:"169345",title:"Dr.",name:"Omolola",middleName:null,surname:"Ayepola",slug:"omolola-ayepola",fullName:"Omolola Ayepola"}]}],mostDownloadedChaptersLast30Days:[{id:"62672",title:"An Overview of Melatonin as an Antioxidant Molecule: A Biochemical Approach",slug:"an-overview-of-melatonin-as-an-antioxidant-molecule-a-biochemical-approach",totalDownloads:3828,totalCrossrefCites:22,totalDimensionsCites:41,abstract:"Melatonin is an endogenous hormone derived from tryptophan that is mainly released from the pineal gland in the dark. Melatonin regulates many biological functions such as sleep, circadian rhythm, immunity, and reproduction. Melatonin has a free radical scavenger, anti-inflammatory, and antioxidant effects. It scavenges reactive oxygen and nitrogen species and increases antioxidant defenses, thus it prevents tissue damage and blocks transcriptional factors of pro-inflammatory cytokines. Due to its small size and amphiphilic nature, it increases the efficacy of mitochondrial electron transport chain and reduces electron leakage. Melatonin prevents degenerative changes in the central nervous system in models of Alzheimer’s and Parkinson’s disease and reduces free radical damage to DNA which may lead to cancer and many other situations. Consequently, melatonin has beneficial effects including stimulation of antioxidant enzymes, inhibition of lipid peroxidation, and so it contributes to protection from oxidative damages.",book:{id:"7328",slug:"melatonin-molecular-biology-clinical-and-pharmaceutical-approaches",title:"Melatonin",fullTitle:"Melatonin - Molecular Biology, Clinical and Pharmaceutical Approaches"},signatures:"Aysun Hacışevki and Burcu Baba",authors:[{id:"248612",title:"Associate Prof.",name:"Aysun",middleName:null,surname:"Hacışevki",slug:"aysun-hacisevki",fullName:"Aysun Hacışevki"},{id:"248614",title:"Ph.D.",name:"Burcu",middleName:null,surname:"Baba",slug:"burcu-baba",fullName:"Burcu Baba"}]},{id:"75377",title:"Pathophysiologic Approach to Type 2 Diabetes Management: One Centre Experience 1980–2020",slug:"pathophysiologic-approach-to-type-2-diabetes-management-one-centre-experience-1980-2020",totalDownloads:777,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This overview summarizes the evolution of pathophysiologic treatment of diabetes type 2 (T2D) in the period of the last 40 years. Randomized Controlled Trials (RCT) and Real World Evidence (RWE) studies resulted in recent Statements of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) in the year 2020. Case reports and studies of a single-centre in Czech Republic are reported. The authors demonstrate the impact of (1) multiple doses of rapid insulin, (2) multiple doses of rapid or ultrarapid insulin analogs (3) continuous subcutaneous insulin infusion (CSII) (4) incretin receptor agonists, (5) fixed combination of insulin degludec with liraglutide (IDegLira) and (6) SGLT2 inhibitor dapagliflozin, on plasma glucose concentration, HbA1c, body mass and patient satisfaction. The importance of therapeutic patients’ education and technology (personal glucometers, continuous/flash glucose monitors, insulin pens/pumps) is emphasized. Most of the observations were already published. Hence, individually adopted education, lifstyle, technical equipment, incretin receptor agonists and/or metformin and/or gliflozins and/or insulin analogs appear to be the core of an effective pathophysiologic approach. Scientific conclusions from RCTs, RWE trials and own clinical case reports may prevail over clinical inertia and induce early implementation of effective methods into routine T2D treatment.",book:{id:"9517",slug:"type-2-diabetes-from-pathophysiology-to-cyber-systems",title:"Type 2 Diabetes",fullTitle:"Type 2 Diabetes - From Pathophysiology to Cyber Systems"},signatures:"Rudolf Chlup, Richard Kaňa, Lada Hanáčková, Hana Zálešáková and Blanka Doubravová",authors:[{id:"278357",title:"Prof.",name:"Rudolf",middleName:null,surname:"Chlup",slug:"rudolf-chlup",fullName:"Rudolf Chlup"},{id:"346119",title:"Dr.",name:"Richard",middleName:null,surname:"Kaňa",slug:"richard-kana",fullName:"Richard Kaňa"},{id:"346120",title:"BSc.",name:"Lada",middleName:null,surname:"Hanáčková",slug:"lada-hanackova",fullName:"Lada Hanáčková"},{id:"346121",title:"BSc.",name:"Hana",middleName:null,surname:"Zálešáková",slug:"hana-zalesakova",fullName:"Hana Zálešáková"},{id:"346122",title:"Dr.",name:"Blanka",middleName:null,surname:"Doubravová",slug:"blanka-doubravova",fullName:"Blanka Doubravová"}]},{id:"61064",title:"Secretions of Human Salivary Gland",slug:"secretions-of-human-salivary-gland",totalDownloads:2766,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"The salivary glands play an important role in our body by the virtue of its ability to secrete saliva. Saliva has a role to play in maintaining the health of the oral cavity and for carrying out physiological functions like mastication, taste perception, speech etc. It also acts as a mirror to the systemic status of an individual owing to its ability to act as a diagnostic fluid for detecting a number of conditions and diseases. Saliva is a potential noninvasive diagnostic fluid for detection of a number of biomarkers of disease and health. Advancement in diagnostic methods has helped in identifying biomarkers of disease in saliva. In order to understand and diagnose pathological changes, a thorough understanding of the salivary gland anatomy, physiology and regulation of its secretion is warranted. This chapter aims to provide the basic understanding of the secretions of saliva.",book:{id:"6246",slug:"salivary-glands-new-approaches-in-diagnostics-and-treatment",title:"Salivary Glands",fullTitle:"Salivary Glands - New Approaches in Diagnostics and Treatment"},signatures:"Anahita Punj",authors:[{id:"226076",title:"Dr.",name:"Anahita",middleName:null,surname:"Punj",slug:"anahita-punj",fullName:"Anahita Punj"}]},{id:"63301",title:"Role of PI3K/AKT Pathway in Insulin-Mediated Glucose Uptake",slug:"role-of-pi3k-akt-pathway-in-insulin-mediated-glucose-uptake",totalDownloads:3541,totalCrossrefCites:11,totalDimensionsCites:27,abstract:"Glucose uptake is regulated by several mechanisms, where insulin plays the most prominent role. This powerful anabolic hormone regulates the transport of glucose into the cell through translocation of glucose transporter from an intracellular pool to the plasma membrane mainly in metabolically active tissues like skeletal muscles, adipose tissue, or liver (GLUT4). This translocation occurs through multiple steps of PI3K/AKT signaling pathway. In this chapter, we will focus on molecular events leading to GLUT4 translocation, starting with activation of insulin receptors through signaling cascade involving phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB) and finally, the action of their effectors. We will present regulatory mechanisms and modulators of insulin-mediated glucose uptake.",book:{id:"7061",slug:"blood-glucose-levels",title:"Blood Glucose Levels",fullTitle:"Blood Glucose Levels"},signatures:"Ewa Świderska, Justyna Strycharz, Adam Wróblewski, Janusz Szemraj, Józef Drzewoski and Agnieszka Śliwińska",authors:null},{id:"70711",title:"Fetal Growth Restriction",slug:"fetal-growth-restriction",totalDownloads:3104,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Fetal growth defect is classified into intrauterine growth restriction (IUGR) and small-for-gestational-age (SGA) fetus based on the estimated fetal weight percentile and Doppler hemodynamic parameters. IUGR pathophysiology and etiology are complex and diverse, highlighting placental insufficiency as a paradigm, which explains its association with other entities of great clinical importance such as preeclampsia. The poor long- and short-term perinatal and postnatal results associated with this context make it necessary to establish an early diagnosis and a therapeutic strategy, which can be challenging due to the compromise between the threat of intrauterine permanence and the prematurity problem. Consequently, a systematic and protocolized diagnostic-therapeutic management, based on scientific evidence, is necessary to determine whether obstetric intervention through a preterm delivery is advisable to improve the perinatal outcomes of these patients.",book:{id:"8224",slug:"growth-disorders-and-acromegaly",title:"Growth Disorders and Acromegaly",fullTitle:"Growth Disorders and Acromegaly"},signatures:"Edurne Mazarico Gallego, Ariadna Torrecillas Pujol, Alex Joan Cahuana Bartra and Maria Dolores Gómez Roig",authors:[{id:"202446",title:"Ph.D.",name:"Maria Dolores",middleName:null,surname:"Gómez Roig",slug:"maria-dolores-gomez-roig",fullName:"Maria Dolores Gómez Roig"},{id:"311835",title:"Dr.",name:"Edurne",middleName:null,surname:"Mazarico",slug:"edurne-mazarico",fullName:"Edurne Mazarico"}]}],onlineFirstChaptersFilter:{topicId:"178",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:8,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:286,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:9,numberOfPublishedChapters:101,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"May 11th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,annualVolume:11410,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,annualVolume:11411,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,annualVolume:11413,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,annualVolume:11414,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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The motor of the society is the industry and the research of this topic has to be empowered in order to increase and improve the quality of our lives.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",keywords:"Machine Learning, Intelligence Algorithms, Data Science, Artificial Intelligence, Applications on Applied Intelligence"},{id:"23",title:"Computational Neuroscience",scope:"Computational neuroscience focuses on biologically realistic abstractions and models validated and solved through computational simulations to understand principles for the development, structure, physiology, and ability of the nervous system. This topic is dedicated to biologically plausible descriptions and computational models - at various abstraction levels - of neurons and neural systems. This includes, but is not limited to: single-neuron modeling, sensory processing, motor control, memory, and synaptic plasticity, attention, identification, categorization, discrimination, learning, development, axonal patterning, guidance, neural architecture, behaviors, and dynamics of networks, cognition and the neuroscientific basis of consciousness. Particularly interesting are models of various types of more compound functions and abilities, various and more general fundamental principles (e.g., regarding architecture, organization, learning, development, etc.) found at various spatial and temporal levels.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",keywords:"Single-Neuron Modeling, Sensory Processing, Motor Control, Memory and Synaptic Pasticity, Attention, Identification, Categorization, Discrimination, Learning, Development, Axonal Patterning and Guidance, Neural Architecture, Behaviours and Dynamics of Networks, Cognition and the Neuroscientific Basis of Consciousness"},{id:"24",title:"Computer Vision",scope:"The scope of this topic is to disseminate the recent advances in the rapidly growing field of computer vision from both the theoretical and practical points of view. Novel computational algorithms for image analysis, scene understanding, biometrics, deep learning and their software or hardware implementations for natural and medical images, robotics, VR/AR, applications are some research directions relevant to this topic.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",keywords:"Image Analysis, Scene Understanding, Biometrics, Deep Learning, Software Implementation, Hardware Implementation, Natural Images, Medical Images, Robotics, VR/AR"},{id:"25",title:"Evolutionary Computation",scope:"Evolutionary computing is a paradigm that has grown dramatically in recent years. This group of bio-inspired metaheuristics solves multiple optimization problems by applying the metaphor of natural selection. It so far has solved problems such as resource allocation, routing, schedule planning, and engineering design. Moreover, in the field of machine learning, evolutionary computation has carved out a significant niche both in the generation of learning models and in the automatic design and optimization of hyperparameters in deep learning models. This collection aims to include quality volumes on various topics related to evolutionary algorithms and, alternatively, other metaheuristics of interest inspired by nature. For example, some of the issues of interest could be the following: Advances in evolutionary computation (Genetic algorithms, Genetic programming, Bio-inspired metaheuristics, Hybrid metaheuristics, Parallel ECs); Applications of evolutionary algorithms (Machine learning and Data Mining with EAs, Search-Based Software Engineering, Scheduling, and Planning Applications, Smart Transport Applications, Applications to Games, Image Analysis, Signal Processing and Pattern Recognition, Applications to Sustainability).",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",keywords:"Genetic Algorithms, Genetic Programming, Evolutionary Programming, Evolution Strategies, Hybrid Algorithms, Bioinspired Metaheuristics, Ant Colony Optimization, Evolutionary Learning, Hyperparameter Optimization"},{id:"26",title:"Machine Learning and Data Mining",scope:"The scope of machine learning and data mining is immense and is growing every day. It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. It is not limited to any particular applications, but contributions are encouraged from all disciplines.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence"},{id:"27",title:"Multi-Agent Systems",scope:"Multi-agent systems are recognised as a state of the art field in Artificial Intelligence studies, which is popular due to the usefulness in facilitation capabilities to handle real-world problem-solving in a distributed fashion. The area covers many techniques that offer solutions to emerging problems in robotics and enterprise-level software systems. Collaborative intelligence is highly and effectively achieved with multi-agent systems. Areas of application include swarms of robots, flocks of UAVs, collaborative software management. Given the level of technological enhancements, the popularity of machine learning in use has opened a new chapter in multi-agent studies alongside the practical challenges and long-lasting collaboration issues in the field. It has increased the urgency and the need for further studies in this field. We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:{title:"Artificial Intelligence",id:"14"},selectedSubseries:null},seriesLanding:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. This series is intended for doctors, engineers, and scientists involved in biomedical engineering or those wanting to start working in this field.",coverUrl:"https://cdn.intechopen.com/series/covers/7.jpg",latestPublicationDate:"May 7th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:3,numberOfPublishedChapters:96,numberOfPublishedBooks:12,editor:{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},subseries:[{id:"7",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:null,institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda",middleName:"R.",surname:"Gharieb",fullName:"Reda Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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