Open access peer-reviewed chapter
Abstract
Endothelial tight junction proteins play an important role in maintaining the integrity of vascular endothelial structure and physiological function. In recent years, studies have found that alterations in the expression, distribution, and structure of endothelial tight junction proteins may lead to many related vascular diseases and pathologies (such as diabetes, atherosclerosis, neurodegenerative diseases, and hypertension). Therefore, related strategies to prevent and/or tight junction proteins dysfunction may be an important therapeutic target. Occludin, as the most representative one among tight junction proteins, is mainly responsible for sealing intercellular junctions, maintaining cell permeability and the integrity of vascular endothelium. Here, we review the published biological information of occludin. We highlight the relationship between occludin and vascular endothelial injury-related disease. At the same time, we show our current knowledge of how vascular endothelial occludin exerts the protective effect and possible clinical applications in the future.
Keywords
- occludin
- vascular endothelial cells
- protective effect
1. Introduction
The normal vascular endothelium is taken as a gatekeeper of cardiovascular health, whereas abnormality of vascular endothelium is a major contributor to a plethora of cardiovascular ailments, such as atherosclerosis, hypertension, myocardial infarction, coronary artery disease [1]. Therefore, it is important to study the occurrence and development mechanism of vascular endothelial injury. Recent studies have shown that alterations in expression, distribution, and structure of endothelial tight junctions (TJ) may lead to atherosclerosis, neurodegenerative diseases, and pulmonary hypertension, suggesting that TJs play an important role in the vascular endothelium [2].
Occludin, the most representative tight junction proteins, can control the permeability of cells by regulating the connection between cells to play a barrier function. Occludin is involved in the formation of cell polarity
Alterations in occludin expression play an important role in vascular endothelial dysfunction. For example, the expression of occludin in retinal vascular endothelial cells of diabetics decreased, resulting in vascular dysfunction such as vascular permeability increased, new vascular formation disorders, and inflammatory response increased, suggesting that the decreased level of occludin may be one of the factors for vascular dysfunction in diabetes [5]. Liu et al. [6] isolated primary mouse retinal endothelial cells for
2. Biological information of occludin
There are four main types of intercellular connections in vertebrates: tight junctions, adhesion junctions, gap junctions, and desmosome junctions. Intercellular tight junctions, which can seal intercellular spaces, control hydronium, water, and other molecular pathways, and maintain cell polarity, as discovered by Farquhar and Palade [8]. Discovery of tight junctions revealed the complexity of cellular internal structural, and cellular tight junction proteins (cingulin [9], Zos [10], Tricellulin, JAM [10], and occludin [11]) further clarify the structural complexity and functional diversity of cells.
2.1 Structure of occludin
Occludin has four transmembrane segments, two extracellular loops (the first extracellular loop rich in tyrosine and glycine and the second extracellular loop rich in tyrosine) and two extracellular loops internal domains (NH2-terminal cytoplasmic domain and COOH-terminal cytoplasmic domain) (Figure 1). The main function of the COOH-terminal cytoplasmic domain of occludin is to mediate the basolateral transport and endocytosis of proteins, while occludin lacking the C-terminus can localize at tight junctions, the tight junctions cannot be assembled correctly and function is lost [12]. In addition, Bamforth et al. [13] found that occludin lacking or truncating the N-terminus of the extracellular domain can still target tight junctions and co-localize with ZO-1, but the function of tight junction barrier disappears, suggesting that the C- and N-terminal domains of occludin are involved in tight junction assembly and play a barrier function. In addition, the two extracellular loop domains of occludin are critical for the localization of cellular tight junctions. Occludin lacking the two extracellular loops is only present on the surface of basal cells but not cellular TJ [14].
Figure 1.
Structural insight into occludin. Occludin shares with general architecture as tetraspan transmembrane proteins colored in a gradient ranging from yellow at the N-terminus [N] to yellow at the C-terminus [C]. aa: Amino acid; G: Glycine; T: Tyrosine; EL1/2, extracellular loops 1 and 2; TM1 to 4, transmembrane domains 1 to 4.
2.2 Tissue distribution and expression regulation of occludin
Occludin is expressed in different cells and tissues with different expression level, and it is related to the function of tissues and organs. Occludin can be expressed in human, rat, mouse and other species, and it is mainly localized in arterial and venous vascular endothelial cells, blood-brain barrier, and blood-retinal barrier [14]. Although the expression of occludin could not be detected at the capillary-endothelial junction in mouse heart and skeletal muscle, occludin was highly expressed in brain capillaries [3], suggesting that occludin is essential for regulating the endothelial permeability of the blood-brain barrier. Morcos et al. [15] confirmed that under physiological conditions, occludin is highly expressed in retinal capillaries. However, in pathological conditions, the expression of occludin in the vascular endothelium will decrease significantly accompanied by different stress responses (inflammation, diabetes, cardiovascular diseases, neurodegenerative diseases, and atherosclerosis), and the permeability of vascular endothelium and the apoptosis of cell will increase [4], which suggests that occludin plays an important role in the blood-retinal barrier. In conclusion, under physiological and pathological conditions, the different expression levels of occludin in different tissues and cells are closely related to the tissue barrier properties.
3. The signaling pathway of occludin exerting the protective effect of vascular endothelium
In recent years, the study of cellular tight junction proteins has increased dramatically. Occludin, the most typical cell tight junction protein, has attracted much attention. A large number of studies have shown that many classical signaling pathways are involved in the regulation of occludin, affecting the distribution and expression of occludin.
3.1 Occludin and mTOR pathway
mTOR, consisting of two distinct complexes (mTORC1 and mTORC2), is a sensor of ATP. mTOR1, a classical metabolic pathway in mammals, is involved in the proliferation and migration of vascular endothelial cells [16] and the occurrence and development of various cardiovascular diseases. Currently, a large number of studies have focused on the role of the mTOR pathway in the regulation of occludin expression [1]. In diabetic rat model, as the phosphorylation level of mTOR increases, the downstream 4EBP1 and S6K1 proteins are activated, and the expression level of ROS is increased, which leads to the reduction of NO production in vascular endothelial cells and the decrease of the expression of occludin protein, and the vascular endothelium is damaged. However, the expression of occludin increased after adding the mTOR inhibitor rapamycin [2, 17] inhibiting the production of occludin
3.2 Occludin and VEGF pathway
The VEGF family consists of five vascular growth factors: VEGFA, VEGFB, VEGFC, VEGFD, and placental growth factor (PIGF). VEGF binds to tyrosine kinase cell receptors (VEGFR1/fms-like tyrosine kinase 1(FLT1), VEGFR2/human kinase insertion domain receptor (KDR)/mouse fetal liver kinase 1 (FLK1), and VEGFR3/ fms-like tyrosine kinase 4 (FLT4)) to exert biological effects. Under physiological conditions, VEGF may cause neovascularization, and aggravate vascular inflammation, vascular endothelial cell proliferation, migration and invasion, and endothelial cell survival [20]. A variety of studies revealed the relationship between the VEGF pathway and occludin: (1) Phosphorylation of occludin S490 could induce endothelial cell VEGF expression and promote endothelial cell proliferation and angiogenesis both
3.3 Occludin and PKC pathway
PKC, a second messenger-regulated serine/threonine kinase, belongs to the AGA kinase family. Studies have shown that PKC can participate in the regulation of vascular endothelial integrity by interacting with the vascular endothelial marker tight junction protein [23]. Presently, a variety of
3.4 Occludin and PKA pathway
PKA, a cAMP-dependent kinase involved in the regulation of vascular endothelium, belongs to AGA kinase. Recently, it was reported in the literature that a novel β-adrenergic receptor agonist [complex 49b]-treated diabetic retinal endothelial cells could activate the PKA signaling pathway, promote the expression of occludin in retinal vascular endothelium, increase vascular tight junctions, and reduce endothelial cell apoptosis [27]. cAMP/PKA signal transduction is involved in the increase of blood-tumor barrier permeability mediated by bradykinin and promotes the up-regulation of occludin expression [28]. Glucagon-like peptide-1 (GLP-1) activates the cAMP/PKA signaling pathway to promote occludin expression and maintain the integrity of the blood-brain barrier in rat primary brain capillary endothelial cells [29].
3.5 Occludin and AMP-activated protein kinase [AMPK] pathway
AMPK is a serine/threonine protein kinase involved in the regulation of cellular and body metabolism. AMPK activation counteracts oxidative stress by inhibiting the production of reactive oxygen derived by NAD[P]H oxidase in endothelial cells [30]. Stimulation of lipopolysaccharide in aging mice can significantly inhibit the activation of AMPK pathway in cerebral vascular endothelial cells, up-regulate the production of NAD[P]H oxidase, and reduce the expression of occludin protein, leading to blood-brain barrier disorders [31]. AMPK kinase inhibits the activation of inflammasome NLRP3 through the mTOR/ULK1 pathway-mediated autophagy, promotes the expression of occludin, and protects the blood-brain barrier in human brain capillary endothelial cells cultured
3.6 Occludin and MAPKs pathway
MAPKs including extracellular signal-related kinases (ERK1/2), p38, and c-Jun N-terminal kinase [JNK] are a family of serine/threonine protein kinases [33]. Under the stimulation of various extracellular factors (such as inflammatory signals), MAPK kinase promotes the activation of nuclear proteins and transcription factors, and regulates gene expression, differentiation, apoptosis and other processes. MAPK kinase is an important intracellular signal transduction that regulates various intracellular functions. Many studies have found that MAPK pathway activation can affect endothelial cell occludin expression and modification in physiological and pathological conditions: (1) Exposure of cerebral microvascular endothelial cells to lipopolysaccharide can affect the p38MAPK/JNK signaling pathway and MMP2 expression, thereby regulating the level of occludin protein in endothelial cells and leading to central nervous system inflammation and brain edema [34]; (2) ERK1/2 inhibits the activation of the NF-κB signaling pathway resulting in the increase of occludin and decrease of endothelial barrier permeability to protect the TJ barrier in human lung microvascular endothelial cells [35]; (3) after lipopolysaccharide stimulates human umbilical vein endothelial cells, it can promote the mRNA and protein expression of CXCL4 and its receptor CXCR3 activates the downstream p38 signaling pathway, thereby inhibiting the expression of occludin in endothelial cells, promoting endothelial cell apoptosis, and increasing endothelial cell permeability [36]; (4) exposure of human umbilical vein endothelial cells to γ-rays can promote the expression of MAPK pathway molecules p38, p53, p21, and p27, induce the activation of NF-κB signaling pathway, and inhibit the expression of occludin in endothelial cells, resulting in the increase of cell permeability, oxidative stress, nitrification, and inflammatory [37]; (5) in human brain microvascular endothelial cells, reduction of occludin can upregulate PI3K/AKT and ERK signaling pathways, and promote cytokine secretion, inflammatory factor activation, and apoptosis protein expression. However, overexpression of occludin can inhibit endothelial cell apoptosis and inflammation [25]. In conclusion, the MAPK signaling pathway is closely related to the regulation of occludin.
4. Protein post-translational modifications (PTMs)
In general, various protein post-translational modifications (PTMs) increase the functional diversity of the proteome through adding covalent functional groups, proteolytically cleaving regulatory subunits, or degrading the entire protein. These covalent modifications of proteins involving in phosphorylation, glycosylation, ubiquitination, nitrosylation, methylation, acetylation, lipidation, and proteolysis have affected all the details of cellular physiology and pathology. The post-translational modifications of proteins further contribute to the biological complexity from genome to proteome. PTMs play an important role in regulating activity, localization, and interaction with cellular molecules (such as proteins, nucleic acids, lipids, and cofactors) [38, 39].
Therefore, better understanding and analysis of protein post-translational modifications may be crucial for the study of cell biology, disease treatment and disease prevention including cardiovascular diseases, several forms of cancers, neurodegenerative diseases and diabetes, etc. [40].
4.1 Post-translational modifications of occludin
In recent years, post-translational modifications of occludin, as representative tight junction proteins, have become a research hotspot. The reported post-translational modifications of occludin include proteolysis, phosphorylation, and ubiquitination, which have all been shown to play vital roles in the course of disease occurrence, development, and convalescence [41, 42].
4.2 Proteolytic degradation of occludin
Studies have found that degradation of tight junction proteins play an important regulatory feature in pathological and physiological tissue remodeling [43]. Basic studies demonstrated that the two fragments of cleaved Occludin released into circulation and the levels of blood occludin correlate well with the extent of blood brain barrier in cerebral ischemic model of rats [44]. In addition, occludin serve as a potential biomarker to predict the severity of acute ischemic stroke, hemorrhagic transformation, and patient prognosis [45]. These results suggested that the degradation of Occludin may be involved in the occurrence and development of many diseases.
4.3 MMPs-dependent degradation of occludin
Matrix metalloproteinases (MMPs) are secreted by astrocytes, endothelial cells, pericytes and peripheral circulating cells and are capable to degrade extracellular matrix (ECM) proteins as well as non-ECM proteins, including cytokines, chemokines, membrane receptors, and antimicrobial peptides [46, 47]. Studied showed that MMPs are related to the development of cancer infiltration and metastasis, inflammatory response, and angiogenesis. Within the endothelial layer, MMPs can degrade intercellular junction molecules (such as cadherin, occludin, and claudins) and intracellular structural proteins (e.g., actins), enhancing the permeability of endothelial barrier [48].
Currently, a number of data have showed that occludin was mainly proteolytically cleaved
4.4 MMP-independent proteolysis of occludin
At present, a large number of data focus on MMPs-dependent occludin degradation; however, there are also some studies showing the existence of MMPs-independent occludin degradation. (1) Qian et al. found that tryptase can act on mouse brain microvascular endothelial cells to promote the production of MMP9/2, degrade the tight junction proteins occludin and Claudin5, and lead to the destruction of the blood-brain barrier [60]. (2) Wan et al. and Runs et al. verified both serine and cysteine peptidases cleavage the occludin with elevation of epithelial permeability, which reveals a pathological mechanism for allergen delivery across lung and nasal epithelial barriers in asthma and allergic rhinitis sufferers [35]. (3) Caspase-mediated cleavage of the occludin C-terminal promotes apoptosis in MDCKs [61]. The studies about the MMP-independent proteolysis of occludin occurred in the epithelial cells; therefore, more research is needed to further define the MMP-independent proteolysis of occludin in endothelial cells.
4.5 Occludin phosphorylation
Protein phosphorylation is a ubiquitous type of post-translational modification, whereby protein kinase catalyzes the phosphorylation reactions by transferring the phosphate group of ATP to the substrate protein amino acid residues, typically serine, threonine, and tyrosine, or bind GTP under the action of signal transduction. It was widely demonstrated that protein phosphorylation is the most basic and the most common key mechanism for regulating and controlling protein biological activity and function [62]. Notably, the phosphorylation status of occludin regulating endothelial barrier protection has been received extensive attention.
More than 40 phosphorylation residues are in human occludin; however, only nine sites are confirmed in cell levels by different kinases on certain stimuli, including Y398, T400, Y402, T403, T404, S408, T424, T438, and S490 [46]. All confirmed phosphorylation residues lie in the occludin C terminal. As early as 1997, Sakakibara et al. firstly observed increased phospho-serine [pSer] and phospho-threonine [pThr] occludin selectively localized to intact epithelial TJs as a detergent-insoluble form [63]. Subsequently, Kale and Elias et al. confirmed occludin phosphorylation on key serine, threonine, and tyrosine residues plays a crucial role in the assembly and maintenance of TJs in Caco-2 and MDCK cells [64, 65]. Dörfel and colleagues in 2013 studied that CK2-mediated phosphorylation [T400A/T404A/S408A] of occludin in MDCK-C11 cells bind with ZO1/2 interaction and protect the epithelial barrier [66]. The regulation of occludin phosphorylation in endothelium has also received extensive attention, with many studies focusing on how the phosphorylation status of occludin regulates the vessel barrier.
Different phosphorylation sites of occludin exerts specific functions in endothelial cells: (1) Antonetti and his colleagues investigate the role of tight junction protein occludin phosphorylation at S490 in modulating barrier properties and its impact on visual function. They found that endothelial-specific expression of the S490A form of occludin completely prevented diabetes-induced permeability to label dextran and inhibit leukostasis. Importantly, vascular-specific expression of the occludin mutant completely blocked the diabetes-induced decrease in visual acuity and contrast sensitivity in the retinas of streptozotocin-induced diabetic mice [67]. (2) Treatment with glutamate increased tyrosine phosphorylation and decreased threonine phosphorylation of occluding in brain microvascular endothelial cells. It affects the redistribution of occludin. These may lead to opening of the blood-brain barrier (BBB) and induce further brain damage [68]. (3) The phosphorylation of occludin and claudin-5 by RhoK at specific sites disrupted the integrity of BBB. Antibodies against specific phosphorylation sites of occludin could be useful reagents for monitoring BBB dysfunction
4.6 Occludin ubiquitination
Ubiquitination, also known as ubiquitylation, refers to the process in which the ubiquitin (a small 76-residue regulatory protein widely expressed in eukaryotes) molecules classify the proteins in cells under the action of a series of special enzymes, choose the target protein molecules from them, and specifically modify the target proteins. These special enzymes include ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin-protein ligase (E3), and degrading enzymes [73]. Ubiquitination plays an important role in protein localization, metabolism, function, regulation, and degradation [73, 74]. At the same time, ubiquitination takes part within the regulation of nearly all life activities, including cell cycle, proliferation, apoptosis, differentiation, metastasis, gene expression, transcriptional regulation, signal transmission, damage repair, inflammation, and immunity [73, 74]. In recent years, studies about the functional role of occludin ubiquitination in diseases have begun to emerge in a burst. And the modification way has become an important regulatory mechanism in epithelial and endothelial function.
Hannelore et al. identified a novel interaction between occludin N-terminal and the E3 ubiquitin-protein ligase Itch, a member of the HECT domain-containing ubiquitin-protein ligases by co-immunoprecipitation
Currently, the study about the regulation of occludin ubiquitination in vascular endothelial function focuses on the following aspects. (1) Murakami et al. demonstrated that Ser-490 phosphorylation of occludin is an essential prerequisite for its ubiquitination in BRECs. The team showed that a C-terminal occludin-ubiquitin chimera was internalized, bypassing the requirement for phosphorylation. Thus, VEGF, through PKCβ-mediated phosphorylation, promotes Itch-mediated ubiquitylation of occludin, which is required for its internalization and degradation, thereby enhancing retinal endothelial permeability [78]. (2) It is well known that blood-spinal cord barrier (BSCB) breakdown is a hallmark of amyotrophic lateral sclerosis (ALS). Results found that mutant SOD1 induced occludin phosphorylation, which promoted the subsequent occludin ubiquitination mediated by the E3 ligase ITCH. Moreover, ubiquitinated occludin interacted with Eps15 to initiate its internalization, then trafficked to Rab5-positive vesicles, and be degraded by proteasomes, resulting in a reduction in cell surface localization and total abundance [79]. (3) Feng et al. showed that the γ-secretase blocker DAPT reduced the permeability of the BBB by decreasing the ubiquitination and degradation of occludin during permanent brain ischemia [80]. Notwithstanding the information already generated about the role of occludin ubiquitination in endothelial cells, several avenues for future investigation still remain. The identification of new ubiquitin enzymes, characterization of tissue and cell-specific occludin ubiquitination, and deciphering the functional rapport between different modification events (e.g., phosphorylation, ubiquitination, proteolysis), will likely typify future studies in this field. This will ultimately yield a fuller understanding of how ubiquitination modifications to occludin affect TJ characteristics and will help to unlock the therapeutic potential of the TJ by identifying new cellular targets for intervention in diseases characterized by barrier dysregulation.
5. The relationship between occludin and vascular endothelial injury-related diseases
Vascular endothelial injury includes vasodilation dysfunction characterized by decreased endothelial NO and structural damage characterized by increased endothelial inflammatory response, endothelial cell apoptosis, and endothelial cell permeability. A large number of studies have found that the abnormal expression and modification of occludin is accompanied by damage to the endothelial structure of blood vessels in tissues and organs, resulting in increased vascular permeability, inflammatory cell infiltration, and apoptosis. Therefore, we will detail the relationship between occludin and diseases related to damage to the arterial vascular endothelial structure in this section.
5.1 Occludin and arterial vascular disease
5.1.1 Occludin and cerebrovascular injury-related diseases
Brain has received extensive attention because it is the most vulnerable to endothelial barrier dysfunction. Under normal circumstances, the blood-brain barrier is a semi-permeable interface, which is important for providing a neuronal microenvironment and exchanging water, ions, gases, and metabolites, but it is not suitable for exogenous harmful substances such as bacteria and viruses [4]. However, many triggers (e.g., inflammation, traumatic brain injury, ischemia) can lead to leakage of the blood-brain barrier, increasing the risk of cerebral edema, nerve damage, cerebral hemorrhage, and further increasing the risk of cerebral ischemia. The brain endothelial cell tight junction protein occludin plays an important role in maintaining the integrity of the blood-brain barrier. For example: (1) Both clinical and basic researchers have found that under cerebral ischemia, and cysteinase can hydrolyze the blood-brain barrier tight junction protein occludin to promote its release into the blood, resulting in an increase of occludin levels in serum. Therefore, serum occludin levels can be used as an indicator for predicting the severity of acute ischemic stroke, hemorrhagic transformation, and prognosis of patients [45]; (2) studies have shown that the increased permeability of the blood-brain barrier in type 1 diabetic mice may be due to the increased level of serum extracellular vesicle occludin, which affects the distribution of occludin in the cerebral vascular endothelial cell membrane [81]; (3) in rat model of traumatic shock, the expression of occludin in cerebral vascular endothelial cells is reduced, which affects the integrity of the blood-brain barrier, the leakage of inflammatory cells, and deterioration of vascular inflammatory response [82]; (4) both
5.1.2 Occludin and coronary vascular injury diseases
Coronary endothelial barrier dysfunction is closely related to ischemic heart disease. Endothelial barrier integrity and function are regulated by a variety of transmembrane proteins, including claudin family proteins, occludin, VE-cadherin, etc. In recent years, basic research on occludin and coronary artery injury-related diseases has found that in mouse model of coronary artery sclerosis, the expression of occludin in arterial endothelial cells decreased, and the atherosclerotic plaque was expanded. Conversely, up-regulation of occludin expression in arterial endothelial cells can alleviate the occurrence and development of plaque [86]. In conclusion, abnormal expression of occludin in coronary endothelial cells is directly related to the occurrence and development of heart disease.
5.1.3 Occludin and pulmonary vascular injury diseases
Pulmonary vascular endothelial cells form a complete cell barrier, participate in the regulation of vascular homeostasis, and maintain the normal operation of the body. Under pathological conditions (diabetes, hypertension, and hyperlipidemia), the pulmonary vascular endothelial barrier is damaged, resulting in vascular endothelial dysfunction and chronic structural damage. Tight junction proteins play an important role in maintaining the integrity of the pulmonary vascular endothelial barrier. As an important component of TJ, occludin has been shown to be down-regulated in a variety of pulmonary vascular injury-related diseases. (1) Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary endothelial cell dysfunction and vascular remodeling. Histological evaluation of mouse model of pulmonary arterial hypertension shows downregulation of occludin expression in pulmonary vessels [87]; (2) the expression of occludin in pulmonary artery endothelial cells of diabetic and hypertensive model mice was reduced, and nitric oxide (NO), superoxide dismutase, and inducible NO synthase were severely imbalanced, suggesting that occludin may be involved in the production of vascular endothelial NO [88]; (3) studies have found that the occludin protein in the pulmonary artery endothelial cells of the rat model of acute lung injury is lost, the endothelial permeability is increased, the vascular inflammatory response is increased, and oxidative stress and other pathological states occur [89]. In conclusion, abnormal expression and distribution of occludin are closely related to pulmonary vascular lesions.
5.1.4 Occludin and renal vascular injury diseases
Kidney is one of the organs with the most abundant distribution of endothelial cells. Under physiological conditions, renal endothelium can mediate signal communication between various parts of the kidney, stabilize renal osmotic pressure, and regulate vascular permeability. Under pathological conditions such as ischemia, inflammation, and sepsis, renal vascular endothelial permeability is increased, renal metabolism is impaired, and the basal layer of endothelial cells is thickened, which induces endothelial damage and leads to plasma leakage. Occludin is involved in maintaining the barrier function of renal endothelial cells, and a large number of basic studies on occludin and renal vascular injury have found that (1) The abnormal expression and distribution of occludin in renal endothelial cells, the imbalance of electrolytes such as sodium, potassium, and chloride, and the deterioration of renal injury exist in the rat model of renal ischemia-reperfusion, suggesting that the abnormal expression and distribution of occludin in renal vascular endothelial cells affect renal function homeostasis [90]; (2) High glucose and high fat stimulate human glomerular endothelial cells, decrease the expression of occludin, and damage renal endothelial barrier function, which leads to development of diabetic nephropathy [91]; (3) renal dysfunction caused by hyperoxia is closely related to renal endothelial tight junction protein occludin [92]. In conclusion, the decreased expression of occludin in renal endothelial cells under pathological conditions may be a new marker of renal vascular injury.
5.1.5 Occludin and other arterial diseases
The blood retinal endothelial barrier maintains the integrity of retinal tissue. The level of occludin in endothelial cells can dynamically regulate the intracellular signal transduction system, promote the transport of nutrients, and limit the transport of harmful substances, which is extremely important for maintaining the blood retinal endothelial barrier. Studies have found that: (1) The phosphorylation of occludin S490 in retinal endothelial cells regulates the proliferation and angiogenesis of retinal endothelial cells [6]; (2) the decreased expression of occludin in endothelial cells of diabetic retinopathy can induce inflammatory cell infiltration, suggesting that the loss of occludin at the blood-retinal barrier leads to increased endothelial cell permeability, which is an important factor for mediating the aggravation of vascular inflammatory responses [93]; (3) when neonatal rats exposed to hypoxia, the expression of occludin in retinal endothelial cells decreased, vacuoles appeared in endothelial cytoplasm, and mitochondrial vacuoles and multivesicles accumulated in capillary lumen, suggesting that occludin was involved in the occurrence of hypoxic stress response [94]; (4) relevant studies have shown that exogenous stimuli (high sugar, long-term high-fat diet, long-term smoking) can inhibit the expression of occludin in the vascular endothelium, resulting in an increase in vascular permeability, which in turn causes the occurrence of oxidative stress in vascular endothelial cells [89]. According to the above research results, it is suggested that the maintenance of blood retinal endothelial barrier integrity is closely related to occludin.
5.2 Occludin and venous vascular diseases
Venous vessels maintain venous barrier function by expressing abundant occludin. Recent studies on occludin in venous endothelial cells have shown that: (1) Serum occludin levels are higher in patients with jugular vein stenosis [95]; (2) Nitta et al. found that in mouse model of retinal vein occlusion, venous vascular inflammation increased, occludin expression decreased, and retinal edema occurred; conversely, inhibiting vascular inflammation could alleviate the decrease in occludin expression and maintain retinal homeostasis [96]; (3) studies on mice with ischemic stroke found that early cerebral venous filling and dilation were associated with occludin displacement and abnormal expression and distribution [97]. In conclusion, the maintenance of the venous homeostasis is inseparable from the regulation of occludin.
6. Conclusions
Occludin, as a cellular tight junction protein, mediates molecular communication between cells and maintains the integrity of various tissues and cells. More and more studies have confirmed that under pathological conditions, various signaling pathways can disrupt the integrity of cell barrier by regulating the expression and distribution of occludin, and participate in apoptosis, inflammation, cardiovascular and neurodegenerative diseases. Occludin plays an important role in cardiovascular disease, but current research also faces great challenges. A variety of classical signaling pathways can regulate the expression and distribution of occludin, but only some studies suggest that occludin can act as an upstream regulatory molecule to affect downstream signaling pathways, whether it affects multiple molecules and signaling pathways is an urgent problem to be solved. At present, most researches focus on occludin participating in cell barrier and maintaining cell integrity. Whether its overexpression plays a positive role in all systems is unknown. Loss of occludin can affect vascular endothelial permeability, leading to pathology such as inflammatory cell infiltration, apoptosis, and oxidative stress. However, whether inflammatory stimulation, apoptosis, and oxidative stress can directly affect the expression, modification, and redistribution of occludin is the current vacancy in current research field and needs further exploration and discovery. Relatively speaking, the research on occludin and vascular endothelial injury-related diseases is still very limited, but there is already relevant evidence that it is a close relationship between them. There is still a large gap in the relationship between occludin and vascular metabolic diseases needs to be filled. With further research in the future, the connection between occludin and many diseases related to vascular endothelial injury will become increasingly clear. In a word, whether it is possible to inhibit or use occludin to develop related drugs and apply them to the treatment of clinical diseases requires further research and discovery.
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