\r\n\tAnimal food additives are products used in animal nutrition for purposes of improving the quality of feed or to improve the animal’s performance and health. Other additives can be used to enhance digestibility or even flavour of feed materials. In addition, feed additives are known which improve the quality of compound feed production; consequently e.g. they improve the quality of the granulated mixed diet.
\r\n\r\n\tGenerally feed additives could be divided into five groups:
\r\n\t1.Technological additives which influence the technological aspects of the diet to improve its handling or hygiene characteristics.
\r\n\t2. Sensory additives which improve the palatability of a diet by stimulating appetite, usually through the effect these products have on the flavour or colour.
\r\n\t3. Nutritional additives, such additives are specific nutrient(s) required by the animal for optimal production.
\r\n\t4.Zootechnical additives which improve the nutrient status of the animal, not by providing specific nutrients, but by enabling more efficient use of the nutrients present in the diet, in other words, it increases the efficiency of production.
\r\n\t5. In poultry nutrition: Coccidiostats and Histomonostats which widely used to control intestinal health of poultry through direct effects on the parasitic organism concerned.
\r\n\tThe aim of the book is to present the impact of the most important feed additives on the animal production, to demonstrate their mode of action, to show their effect on intermediate metabolism and heath status of livestock and to suggest how to use the different feed additives in animal nutrition to produce high quality and safety animal origin foodstuffs for human consumer.
",isbn:"978-1-83969-404-2",printIsbn:"978-1-83969-403-5",pdfIsbn:"978-1-83969-405-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"8ffe43a82ac48b309abc3632bbf3efd0",bookSignature:"Prof. László Babinszky",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10496.jpg",keywords:"Technological Feed Additives, Feed Industry, Quality of Compound Feed, Non-Antibiotic Growth Promoter, Product Quality, Additive Enzymes, Digestibility of Nutrients, NSP Enzymes, Farm Animals, Livestock, Immunity, Microbiome",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 24th 2020",dateEndSecondStepPublish:"December 22nd 2020",dateEndThirdStepPublish:"February 20th 2021",dateEndFourthStepPublish:"May 11th 2021",dateEndFifthStepPublish:"July 10th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Professor Emeritus from the University of Debrecen, Hungary who authored 297 publications (papers, book chapters) and edited 3 books. Member of various committees and chairman of the World Conference of Innovative Animal Nutrition and Feeding (WIANF).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.jpg",biography:"László Babinszky is Professor Emeritus of animal nutrition at the University of Debrecen, Hungary. From 1984 to 1985 he worked at the Agricultural University in Wageningen and in the Institute for Livestock Feeding and Nutrition in Lelystad (the Netherlands). He also worked at the Agricultural University of Vienna in the Institute for Animal Breeding and Nutrition (Austria) and in the Oscar Kellner Research Institute in Rostock (Germany). From 1988 to 1992, he worked in the Department of Animal Nutrition (Agricultural University in Wageningen). In 1992 he obtained a PhD degree in animal nutrition from the University of Wageningen.He has authored 297 publications (papers, book chapters). He edited 3 books and 14 international conference proceedings. His total number of citation is 407. \r\nHe is member of various committees e.g.: American Society of Animal Science (ASAS, USA); the editorial board of the Acta Agriculturae Scandinavica, Section A- Animal Science (Norway); KRMIVA, Journal of Animal Nutrition (Croatia), Austin Food Sciences (NJ, USA), E-Cronicon Nutrition (UK), SciTz Nutrition and Food Science (DE, USA), Journal of Medical Chemistry and Toxicology (NJ, USA), Current Research in Food Technology and Nutritional Sciences (USA). From 2015 he has been appointed chairman of World Conference of Innovative Animal Nutrition and Feeding (WIANF).\r\nHis main research areas are related to pig and poultry nutrition: elimination of harmful effects of heat stress by nutrition tools, energy- amino acid metabolism in livestock, relationship between animal nutrition and quality of animal food products (meat).",institutionString:"University of Debrecen",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Debrecen",institutionURL:null,country:{name:"Hungary"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"25",title:"Veterinary Medicine and Science",slug:"veterinary-medicine-and-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"185543",firstName:"Maja",lastName:"Bozicevic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/185543/images/4748_n.jpeg",email:"maja.b@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"53219",title:"Therapeutic Angiogenesis: Foundations and Practical Application",doi:"10.5772/66411",slug:"therapeutic-angiogenesis-foundations-and-practical-application",body:'\nBlood vessel growth is a natural process driven by multiple stimuli of which hypoxia is one of the strongest inducing potent response until O2 pressure is normalized by the blood coming through de novo formed vasculature. However, a large group of diseases is caused by hypoxic or ischemic state of tissue. These include peripheral artery disease (PAD) and intermittent claudication (IC), coronary heart disease (CHD), myocardial infarction (MI) and ischemic stroke. Accompanied by endothelial dysfunction and age-related reduction of angiogenic response, they result in disabilities and mortality rate of 25–25% annually. Existing strategies for surgical bypass or endovascular interventions have limited efficacy as far as a cohort of non-option patients expands reaching 25–50% after certain extent of disease progression. Moreover, long-term prognosis after most interventions is negative as grafts undergo restenosis and vascular biocompatible prosthetics are yet to come for wide application. This drew attention of physicians and researchers to the concept of angiogenic therapy to stimulate body’s own resource and form new blood vessels to relieve ischemia. During recent decade the field of biomedicine known as therapeutic angiogenesis evolved rapidly using protein delivery, gene therapy, cell therapy and tissue engineering for induction of vessel growth and overview of its\x3c!-- Please define the abbreviation “AGENT, RAVE, OPTIMIST, EuroOPTIMIST, TAMARIS, STAT, TRAFFIC, SDF-1α, TALISMAN-201” at its first mention.
Postnatal growth of blood vessels is mediated by three mechanisms: vasculogenesis, angiogenesis and arteriogenesis [1]. Vasculogenesis is de novo formation of vasculature from specific progenitor or stem cells; however, it is attributed to prenatal period and after birth its role is unclear [2] and major extent of blood vessel formation involves two other mechanisms focusing our attention on them. Molecular and cellular basics underlying these processes became the cornerstones of therapeutic angiogenesis and become the source of novel objects for applied researchers and translational medicine.
\nAngiogenesis is the formation of a blood vessel de novo, yet in contrast to vasculogenesis, it relies on migration, proliferation and sprouting of existing endothelial cells (EC) comprising capillaries. The latter are small (8–15 μm) vessels lacking tunica media responsible for majority of tissue blood supply and O2/CO2 exchange [3]. Reduction of tissue O2 induces angiogenesis response in health (intense exercise, tissue growth, etc.) and in disease: in the case of interrupted or declining supply due to atherosclerotic lesions or anemia [4]. Under normal condition, capillaries are stabilized by autocrine and paracrine stimuli (Notch1 axis, angiopoietins, thrombospondin, angiostatin, transforming growth factor (TGF)-β, etc.) that balance influence of pro-angiogenic cytokines within blood vessels’ vicinity (vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF)). Hypoxia dislodges this balance toward angiogenic events and this is mediated by O2-sensitive system existing in a variety of cells including EC themselves, smooth muscle cells (SMC), pericytes and fibroblasts. Cells respond to hypoxia via a system of hypoxia-induced factors (HIFs) [5]—a group of heterodimeric transcription regulators controlled by O2-sensitive prolyl hydroxylases. Briefly, stability of HIFs is increased drastically in hypoxic environment resulting in their binding to hypoxia-responsive elements within promoter regions of genes increasing their expression [6]. HIF-dependent genes include a vast array of cytokines stimulating EC proliferation, blood vessel sprouting and, thus, labeled “angiogenic growth factors” [7, 8]. The latter include soluble growth factors associated with EC proliferation and differentiation (acidic FGF (aFGF), basic FGF (bFGF), HGF, VEGFs) [9, 10] and cytokines bound to extracellular matrix (ECM) and released during its cleavage [11]. These changes induce EC proliferation and migration forming a vascular sprout guided by a “tip cell.” This cell follows a gradient of concentration and produces matrix metalloproteinases (MMPs) and urokinase (uPA) to cleave the ECM [12], releasing growth factors and basically tunneling ECM followed by “stalk cells” that form a new capillary [13]. After lumen formation occurs normalized blood supply switches off hypoxic stimuli, “tip cells” lose their phenotype and proteolytic potential [14] commencing microenvironment stabilization. Expression of tissue metalloproteinase inhibitors and Dll4-Notch1 axis [15] induction in EC is followed by reestablishment of a balanced state between pro- and antiangiogenic molecules in the tissue leaving a new capillary-sized blood vessel [16]. However, it should be mentioned that this sequence of events never occurs as a perfectly tuned mechanism. “Stub” branches are formed and must be removed, certain “tip cells” fail to form a sprout and maturation of vascular network includes dissociation of certain anastomoses [16], which overall describes angiogenesis as a dynamic process modulated by multiple stimuli [17]. Finally, under influence of stabilizing signals from surrounding EC, pericytes and stromal cells, the vascular bed returns to normal steady state.
Arteriogenesis is triggered by rise of shear stress after an occlusion and induces collateral vessel remodeling forming a bypass 20–100 μm in diameter with developed tunica media. Arteriogenesis may occur gradually (e.g., in increasing stenosis of a large-caliber artery) or can be triggered by a rapidly developed occlusion with both situations are to result in effective blood flow delivery “around an obstacle” to distal portions of the limb or organ [18]. Certain studies show that collateral remodeling can be reversible till certain point of this process in case shear stress drops to normal after thrombolysis or surgical thrombectomy [19]. Effective arteriogenesis may bypass up to 30–40% of basal blood flow in critical stenosis and thrombosis, which is sufficient for tissue survival. However, its efficacy is drastically reduced in disease and with aging [20]. Smoking-related hypercoagulation, hypertension and diabetes also limit arteriogenic response resulting in critical level of ischemia and tissue loss [21].
\nAfter pressure rise in collaterals above the site of thrombosis, shear stress induces EC membrane deformation and flow-sensitive ion channels activate downstream MAP-kinase (ERK1/2, Rho, etc.) phosphorylation and expression of, growth factors, adhesion molecules and chemokines (interleukin-8, macrophage chemoattractant proteins, etc.) [20]. Eventually leukocytes begin to “roll” on EC surface resembling inflammatory changes of vascular function and infiltrate the collateral’s wall [22]. Pivotal role in wall thickening is played by monocytes and their differentiated forms—macrophages and dendritic cells. Their function is not limited to ECM and basal lamina cleavage by MMP and uPA production to destabilize the collateral and make it “flexible” [23], but they seem to profoundly change the properties of the blood vessel by induction of SMC proliferation and hypertrophy [24]. Under these influences, media thickness may increase 3- to 4-fold and collateral vessel’s volume can enlarge up to 20-fold [25]. Moreover, monocytes produce a wide spectrum of angiogenic and mitogenic cytokines, some of which have antiapoptotic properties required for tissue protection [26]. The role of monocytes and macrophages has been especially emphasized in cardiac arteriogenesis where immunosuppressive steroid hormones [27], anti-inflammatory therapies and even aspirin [28] have been shown to negatively impact the outcomes and collateral remodeling. Toxic depletion of monocytes by clodronate reduced arteriogenesis in cryo-injured myocardium and led to decreased ventricular function and higher mortality [29]. As collaterals increase shear stress stimulus is relieved and EC reduce production of chemokines and lose their “adhesive” phenotype. Macrophages limit production of proteolytic enzymes and start ECM reconstruction producing collagens, laminin and elastin and forming adventitial and medial portions of a new arterial vessel.
\nTypically, we mention “therapeutic angiogenesis” referring gene or cell therapy to relieve ischemia. Nevertheless, one may see that angiogenesis and arteriogenesis share common mediators—namely growth factors and enzymes, ECM components, EC activation, etc. Eventually, for adequate function therapeutic angiogenesis has to rebuild both—medium/large-caliber arteries providing influx of blood and capillary-sized vessels that deliver it to the cells.
After the discovery of proteins with angiogenic effects, the concept of their therapeutic application was introduced by the 1990s and a vast array of animal studies was published to demonstrate angiogenic efficacy of recombinant protein delivery. Going beyond the VEGF family, experimental works showed induction of angiogenesis by FGFs, HGF, PDGF and placental growth factor (PlGF) in small rodents and rabbits [30, 31]. Injection of these cytokines to ischemic tissue or blood vessels increased perfusion and vascular density. However, promise of this method was questioned as far as achievement of local pharmacological concentration by injection was extremely expensive (especially for human body mass) and half-life of most cytokines was too low to render potent effects [32]. Furthermore, little was known on pharmacokinetics of recombinant proteins delivered intravascularly and their potential involvement in tumor growth and chance of “washout” to systemic blood flow raised safety concerns.
\nIn 2000, the first clinical trials of recombinant human bFGF were initiated in PAD/IC patients after a pilot study showing safety and tolerance of intra-arterial delivery of bFGF solution. Unfortunately, it was halted prior to completion of protocol due to urinalysis data revealing proteinuria in bFGF-treated subjects and no positive changes of endpoints at the moment when the trial was put to a premature end [33]. The final attempt to achieve success in the field was the Therapeutic angiogenesis with recombinant fibroblast growth Factor-2 for intermittent claudication (TRAFFIC) randomized placebo-controlled trial in patients with PAD showing significant improvement in walking time and ankle-brachial index (ABI) in bFGF group. However, safety profile was compromised and yet no cardiac adverse effects or evidence for tumor formation was found in recurrent cases of proteinuria and signs of nephrotoxicity were an issue [34].
\nThese results were as disappointing as valuable for the field and suggested that gene therapy with its local sustained expression of desired protein is the best alternative possible [32]. Recently, no further attempts to implicate protein delivery for therapeutic angiogenesis were made in clinics and advantages of other methods are exploited to patients’ benefit.
Gene therapy relies on delivery of genetic information by introduction of nucleic acids to target cells/tissues using vector systems. This results in local expression and production of desired protein over a certain period depending on vector used and properties of tissue. First experiments indicating possibility of in vivo gene delivery using simple injection of a recombinant plasmid DNA (pDNA) opened the gate for hundreds of studies published within the last two decades [35].
\nAs far as the “cornerstone” of gene therapy is the vector system, a brief overview of existing options is required. General concept in the field is that all vectors can be divided into “viral” and “nonviral” subgroups covering nearly any possible way of genetic material delivery. Among nonviral vectors, pDNA is the most widely used due to its long-studied safety profile, ease of production and low immunogenicity allowing repetitive administration [31, 36]. Moreover, plasmids are feasible for combined delivery of several growth factors by mixing them in a formulation or generating a multicistronic vector. However, low transfection efficacy (0.5–2.0% in various tissues) in large mammals including human is an efficacy-limiting issue for pDNA [37]. Viral delivery systems comprise a broad spectrum of recombinant or chimeric viruses of different capacity having a great potential. The latter is due to high transduction efficacy and long expression period accompanied by tissue tropism in certain viruses. However, disadvantages are safety issues: immune reactions and risk of carcinogenesis due to integration to host genome. The most widely spread vectors include\x3c!-- Please check the following sentence "The most widely spread include…" for clarity.
Period of growth factor-based gene delivery dates back to the seminal study by Dr. J. Isner [43] who used injection of pDNA encoding VEGF-A 165 (VEGF165) isoform to succeed in treatment of a non-option patient with critical limb ischemia. “First in-human” data were supported by Baumgartner et al. who found increased collateral formation after intramuscular delivery of VEGF165 and EC proliferation in amputation material providing proof of mechanism [44]. Later a number of vectors using VEGF-A and its isoforms were evaluated in experimental and clinical trials making it the most intensively studied object in therapeutic angiogenesis.
\nAmong numerous clinical examples, one may highlight the first “head-to-head” comparison of adenovirus with VEGF165 (Ad-VEGF165) and liposome-packed pDNA-VEGF165 in PAD patients undergoing angioplasty. The trial showed low clinical efficacy of both approaches—Rutherford severity class stayed comparable to control group yet vascular density was increased after treatment [45]. This and other studies using catheter delivery hinted that this method lacks site specificity and intramuscular injection technique was generally adopted. However, initial Groningen double-blind placebo-controlled trial intramuscular injection of pDNA-VEGF165 in PAD patients with diabetes mellitus failed the primary endpoint (amputation rate), yet improvements in ulcer healing, TcO2 and ABI were observed [46].
\nLater, Regional angiogenesis with VEGF (RAVE) trial was the first double-blind placebo-controlled trial of VEGF-A 121 isoform (VEGF121). This cytokine is considered to have better solubility than VEGF165 isoform as it lacks a heparin-binding domain [47]. Key feature of this study was an attempt to perform dose optimization of Ad-VEGF121 dividing 105 patients with PAD/IC into three subgroups that received a single session of 20 intramuscular injections of AdVEGF165 delivering low dose (4 × 109 particles), high dose (4 × 1010 particles), or placebo. Final assessment after 12 weeks revealed no significant differences in endpoints between control and treatment subgroups, yet dose-dependent increase of edema adverse effect was observed. Indeed, since first studies delivery of VEGF-A isoforms was haunted by evidence of edema formation due to its influence on endothelial permeability [48] with certain authors claiming this was a putative reason for low efficacy of therapy [49].
\nTrials in MI patients were initiated as early as in 1998 using a pDNA-VEGF165 showing good safety profile and no positive changes [50]. It was followed by Kuopio Angiogenesis Trial [51] using a comparative design with Ad-VEGF165 or pDNA-VEGF165 delivery by intramyocardial injection during transcutaneous angioplasty. In this trial, no differences between control and treatment groups were found, yet at 6 months after injection of Ad-VEGF165, myocardium perfusion was higher than pDNA-VEGF165, which was attributed to its high transduction efficacy. EuroInject One trial gave similar results showing no significant improvement of myocardial perfusion after injection of pDNA-VEGF165, yet local contractility was higher than control [52].
\nTrials using delivery of HGF were initiated and conducted by Dr. Morishita’s group aiming to treat PAD by intramuscular injection of pDNA-HGF. Encouraging results in animal models [31, 53] promoted clinical translation and after safety assessment a Phase II trial was initiated comparing single and repeated dose of pDNA-HGF in favor of multiple injections: only this dosing regimen showed improvement of TcO2 compared to control [54]. Further results in a placebo-controlled I/IIa phase trial showed good safety with no traces of secreted HGF in peripheral blood and repeated injection of 8 mg pDNA-HGF showed significant improvements of secondary endpoints (ulcer size, ABI and pain reduction) [55]. Similar results were obtained in a placebo-controlled trial in PAD patients where by the end of week 12, 70% decrease of ulcer size was observed [56]. Further attempts to increase efficacy included the use of a bicistronic plasmid encoding two forms of HGF named dHGF and cHGF. They were evaluated in animal models showing better perfusion after expression of dHGF + cHGF than each one alone [57]. Clinical trial of this approach in PAD patients showed that multifocal intramuscular injections of 4–16 mg of pDNA-dHGF/cHGF resulted in improvement within 3 months independently of dose: rest and walking pains reduced and a trend toward ulcer healing and increase of TcO2 was observed [58].
\nOverall, we may expect HGF-based drugs to become the first widely marketed for PAD—in Japan it has been registered under “Collategene” name and now undergoes stage III clinical trial in PAD cohort. Furthermore, despite HGF has never been tested for MI treatment in clinical settings, preclinical assessments indicate that it may be effective as it has antifibrotic and angiogenic mode of action that can be a good option for this disease or subsequent ventricular failure due to tissue scarring [53, 59].
\nFibroblast growth factor has been the first used in protein delivery and gene therapy studies were to follow as soon as it gained attention. Therapeutic angiogenesis leg ischemia study for the management of arteriopathy and non-healing ulcer (TALISMAN-201) have evaluated pDNA-FGF-1 in no-option PAD patients [60] and showed improvements as decreased amputation rate within 1 year after treatment [61] and its prospective part showed reduced general mortality in treated subjects [62]. However, phase III placebo-controlled “TAMARIS” (n = 525) trial drew disappointing results and all primary endpoints including amputation events failed to improve after treatment by pDNA-FGF-1 [62, 63]. Similar results obtained in OPTIMIST and EuroOPTIMIST trials indicated safety and lack of efficacy after treatment and lead to wrapping up of this prospective drug testing. Nevertheless, in a follow-up stage, important safety data showing no increased cancer, stroke, or MI in FGF-treated patients was obtained and positively impacted new proceedings in the field [64].
\nIn MI patients, FGF-4 was delivered using an intracoronary injection of an adenovirus with this gene (Ad-FGF-4) in an Angiogenic gene therapy (AGENT) trial. Result evaluation showed that the only subgroup with reduced size of ischemic myocardium after treatment was female patients when compared to male subgroup. The authors speculated that it may be attributed to higher extent of microcirculatory disorders in females [65, 66] accompanied by fewer critical stenosis typical in men [67]. As far as FGF-4 is known to positively influence endothelial function, this might have been the mechanism for observed changes in the trial. Among other therapeutic factors used for stimulation of angiogenesis, HIF-1α and development endothelial locus-1 (DEL) are both worth a mention as far as they made it to the bedside in recent years using adenovirus or pDNA vectors. However, trials showed minimal improvement in PAD patients and further evaluations were ceased up to date [68, 69].
\nOverall despite failure to show expected efficacy in clinic, gene therapy is safe and well tolerated by patients showing little evidence although long-term evaluations are yet to be completed. Key obstacle in pDNA-mediated gene therapy relates to transfection efficacy and thus protein production levels after administration [70]. Viral vectors show some promise in solving the problem, yet optimization of dosage regimen, delivery routes and administration protocols also provide a field for further development.
\nFrom the point of translational potential, pDNA-based gene therapy has the best safety profile and the best results are definitely yet to come in the following years yet points for improvement are obvious. Efficacy improvement in gene therapy can be achieved by combined approaches basing on the point that angiogenesis is a dynamic process controlled by numerous cytokines, each playing its party in initiation/cessation of different stages. This puts the basis for combined gene therapy to treat ischemia with higher efficacy and it has been supported by experimental findings using VEGF165 combined with another pro-angiogenic growth factor: bFGF [71], PDGF [72], angiopoietin-1 [73], or Stromal cell-derived factor-1α (SDF-1α) [74]. Our previous experience in mouse hind limb ischemia model showed that combination of VEGF165 and uPA [75] or HGF [76] induced angiogenic response more effectively than each factor alone or allowed to reduce pDNA dose for combined delivery [75]. A crucial transcription factor in angiogenesis, HIF-1α, was also used for combined gene therapy with VEGF165 showing good results in animal model [77] as well as bFGF + heme oxygenase-1 (HO-1) [78]. Regarding the latter, it is known that HO-1 is an important regulator of endothelial function with protective function. Its expression is known to induce angiogenesis in ischemic tissues and blockade or knockout reduces EC proliferation and motility and thus capillary growth [79].
\nTriple combined gene therapy has not been evaluated for angiogenesis, yet a study was published where controlled release scaffolds containing a mix of VEGF165, HGF and angiopoietin-1 or their double combinations were evaluated for enhancing efficacy of endothelial progenitor cell (EPC) therapy. Triple combinations resulted in significantly higher SMC counts indicating more efficient vessel stabilization due to angiopoietin-1 effects on perivascular cell chemotaxis [80].
\nAuthors claimed that the use of VEGF165 + another cytokine typically leads to decreased edema and vascular permeability: this has been shown for a well-known stabilizing cytokines—angiopoietin-1 [73] and HGF [81]. Thus, another rationale for combined therapy is decrease of certain “side effects” observed in “monotherapy” by VEGF as a key player in gene therapy. The latter point is not limited to reduction of adverse reactions, but also arises from a large spectrum of pleiotropic effects of cytokines. For example, VEGF may act as a pro-inflammatory cytokine by induction of nuclear factor κ-B, while HGF [82] or angiopoietin-1 shows antagonistic effects leading to reduction of VEGF-driven cell adhesion and inflammation [83]. Indeed, this has been confirmed in a number of in vitro tests and skin inflammation model indicating that these properties may be utilized for development of next-generation gene therapy drugs for angiogenesis exploiting pleiotropy of cytokines besides their main angiogenic effect. Another approach is delivery of growth factors in two sessions apart in time: for example, pre-treatment by angiopoietin-1 pDNA resulted in better angiogenic response after subsequent pDNA-VEGF165 injection in mouse hind limb ischemia model hinting time of administration as an important factor for efficacy [84].
Cell therapy is a promising tool for regenerative medicine and therapeutic angiogenesis using progenitor or stem cells’ ability to self-renew and mediate tissue repair. For potential use of cell therapy for vascular repair, one of the most intriguing findings was the discovery of endothelial progenitor cells (EPC) in circulating blood which hinted involvement of postnatal vasculogenesis in perfusion restoration [85]. However, further works sparkled controversy about EPC phenotype, origin [86], role in recovery from disease and even existence. Report by Prokopi et al. [87] claimed that EPC can be false-detected as endothelium-like (CD31/vWF+) monocytes in cultures due to phagocytosis of residual platelets rich with these protein markers.
\nClinical trials up to date focus on delivery of bone marrow (BM) cells for induction of angiogenesis. These studies evaluated effects of BM mesenchymal stem cells (BM-MSC) or mononuclear cells (BM-MNC) delivered by intramuscular or intravascular injection in PAD patients. Most studies supported efficacy and indicated improvement in evaluated endpoints: ABI, pain-free walking distance, TcO2, ulcer healing, or amputation-free period. However, some pivotal trials are to be mentioned in detail for better understanding of the field’s status.
\nFirst set of crucial data was obtained during “head-to-head” comparison of different cell types to identify the optimal cell source. In a double-blind randomized study, administration of BM-MSC to diabetic PAD patients with foot ulcerations showed efficacy superior to BM-MNC [88]. Subjects that received BM-MSC showed complete ulcer healing 4 weeks earlier than BM-MNC; perfusion assessment, pain-free walking time, ABI and angiography data also spoke in favor of BM-MSC as a more effective cellular angiogenic agent [88].
\nHowever, limitation of BM-based treatment is invasive procedure to obtain material and alternative approach was proposed using peripheral blood mononuclear cells (PB-MNC) mobilized by granulocyte colony-stimulating factor (G-CSF) pre-administration. Feasibility of this approach was obvious and a trial was initiated to confirm its efficacy compared to BM-MNC enrolling a total of 150 patients split in two groups. After 12 weeks of observation, PB-MNC patients showed significantly higher limb temperature, ABI and reduced rest pains than BM-MNC. Yet no difference was found in TcO2, ulcer healing rate and amputation frequency hinting that two methods showed comparable efficacy profile with a trend to PB-MNC application due to feasibility and endpoint improvements [89]. Interestingly, a trial of conventional therapy + G-CSF monotherapy was compared to BM cells and in these groups, improvements in ABI and TcO2 were comparable and significantly better than in conventional drug therapy control. This was an intriguing finding which showed that mobilization of endogenous mononuclear cells (MNC) was sufficient to replace BM grafting and injection [90].
\nAnother source of cells for therapeutic angiogenesis is adipose-derived mesenchymal stromal cells (AD-MSC). Despite sources of mesenchymal stem cells (MSC) are not limited to adipose tissue, these adult stromal cells can be isolated from samples obtained during lipoaspiration or surgery. Taken together with ease of expansion, well-established phenotype and abundance in healthy individuals, it makes AD-MSC an excellent object for autologous and allogeneic use for angiogenesis stimulation [91]. Published experimental studies show that AD-MSC use their paracrine potential for induction of angiogenesis and support of collateral remodeling [92]. This is referred as “bystander effect” to emphasize that AD-MSC render their effects by paracrine mechanism in contrast to previously existing opinion about their significant ability to differentiate into specific vascular cells and EC in particular [93].
\nThese cells have not been evaluated in PAD or MI clinical trials yet and considered to be a very attractive option to complement existing strategies. Certain factors limiting potency of AD-MSC exist including donors’ age [94], comorbidities and effects of ex vivo culture [95]. However, improvement can be achieved by manipulation of cells’ paracrine activity, e.g., by viral transduction to increase expression of cytokines forming an “alliance of gene and cell therapy” for higher efficacy [96]. This approach has become possible after development of effective viral gene delivery systems as far as pDNA transfection in primary human cultures was extremely low or at the level of toxicity exerted by transfection reagents [97]. Modification of cells intended for therapy use in performed ex vivo after sufficient amount of material is obtained in appropriate culture condition. Selection of a viral vector depends on safety precautions and vector capacity for genetic material; however, cDNA of most angiogenic cytokines “fit” into commonly used adenoviruses or adeno-associated virus (AAV).
\nThis method has been tested in animal models of ischemia using exogenous delivery of VEGF165 [98], insulin-like growth factor-1 [99], HO-1 [100], or other genes to different types of cells: AD-MSC, EC, BM-MSC, etc. In majority of reports, modification resulted in improvement of response after delivery to ischemic tissue. In our experience, administration of human VEGF165-expressing AD-MSC to ischemic limb of immunodeficient mice resulted in enhanced perfusion and vascular density superior to control cells. Furthermore, muscle necrosis was minimal in this group indicating enhanced blood supply and antiapoptotic effects of VEGF165 as mode of action [98].
\nApplication of modified stem cells for induction of angiogenesis may be limited in coming years unless safety of modification and full extent of its influence on biological properties of cells is understood. Ex vivo modified cells are widely used for treatment of oncology and hereditary disease where benefit for patient overwhelms existing risks [101]; however, for treatment of PAD and MI, additional measures of precaution will be required prior to active clinical trials. Nevertheless, recently a group led by Dr. J. Laird began a phase I trial to evaluate the use of VEGF-expressing MSC in patients with critical limb ischemia. The trial is now ongoing with expected completion in 2017 and preclinical data indicated good safety profile with long-term expression of VEGF in MSC after viral modification [102]. Recent progress in virus biology and gene engineering allowed development of safer vector systems with controlled expression, integration, or directed insertion to genomic “safe harbors” where they induce minimal to none disturbances [103]. Preclinical evaluation of these systems is expected to give more data on long-term impact of modification and facilitate translation.
Cell sheets (CS) were first introduced by Dr. Okano’s group and occupied a niche between 3D tissue engineering and 2D cell cultures used to obtain therapeutic cellular materials [104]. Briefly, CS is an attached mono- or multilayered xeno-free construct that consists of viable cells with ECM produced by these cells. Application of this method allowed to circumvent a crucial setback observed in a number of experimental works—poor survival of cells used for therapeutic interventions. One of main reasons for this is procedure of detachment by proteolytic enzymes leading to disruption of ECM (along with deposited cytokines) and loss of intercellular contacts resulting in anoikis and high prevalence of cell death aggravated by passage of cells through a catheter or needle causing mechanical damage. Loss of cells implanted to the tissue by injection in suspended form is estimated as 40–75% within the first 3 days [105], while CS limits this damage to minimum keeping the cells viable after delivery and enhancing their engraftment [106]. Furthermore, ECM proteins delivered as a part of the construct are known to have a beneficial impact on regeneration and do not have toxic or immunogenic features of chemical or xenogeneic scaffolds. Generation of CS is possible from MSC, fibroblasts, EC, skeletal myoblasts, induced pluripotent stem cells and cardiomyocytes derived from them, BM cells and cardiac progenitor cells [107]—literally, any adherent cell culture after it produces enough ECM to stand mechanical manipulation [108]. CS can be used to cover a significant surface making it a good technique for superficial lesions, cardiomyoplasty and ophthalmologic and microsurgical manipulations. Numerous clinical trials are being run in Japan these years to reveal their full potential in a wide array of disorders [109].
\nIn relation to angiogenesis, this technique was evaluated in MI models using CS from skeletal myoblasts, AD-MSC, or cardiac progenitor cells showing their ability to generate vascularized additional layer of tissue and facilitate vascular growth in underlying tissue [110, 111]. This resulted in improved ventricular function, limited MI size and fibrosis and favorable outcomes in experimental animals. Comparative study of CS vs. injection of suspended cells showed CS to be superior in terms of most functional and histological endpoints analyzed and using a bioluminescent method, the authors reported higher survival of transplanted rat neonatal cardiomyocytes after CS delivery compared to injection [112]. Recently, clinical application of CS from autologous skeletal myoblasts has begun to treat severe heart failure patients with left ventricular assist devices. Delivery of multilayered constructs resulted in ejection fraction increase sufficient to remove the device and postpone heart transplant as well showing good potential of this approach [113].
\nIn limb ischemia and diabetes, CS are generally considered to be a tool for ulcer treatment and indeed numerous clinical trials have been initiated within last years. However, our group has been extensively investigating application of CS as an angiogenic therapy in PAD. We have found that subcutaneous delivery of CS from AD-MSC to mice with limb ischemia resulted in robust angiogenic response and CS were superior to dispersed cells in terms of tissue perfusion and vessel density [114]. This piece of evidence provided basis for CS application in PAD indicating that their potential is not limited to cutaneous healing but that paracrine factors are capable to induce angiogenic response in ischemic muscle. Our data were supported almost at the same time in a study by Bak et al. who used mixed CS from SMC and EC for successful treatment of experimental limb ischemia in mice by subcutaneous delivery [115].
\nFurther improvement of CS potential is possible by application of ex vivo modification to express growth factors and discussed above. Our group’s experience with viral vectors expressing VEGF165 suggested robust increase of angiogenesis in MI and limb ischemia after delivery of sheets from AD-MSC expressing VEGF165 after viral transduction [114, 116]. Effect of these constructs was superior to control CS and we observed no changes in immune response to genetically modified sheets or cell proliferation/viability within them [114].
\nOverall, application of CS for therapeutic angiogenesis is a new field and its expansion is expected within next years. These constructs are feasible from a translational point of view as far as they do not contain xenogeneic, artificial, or cadaveric materials circumventing many ethical and safety problems in translation.
Overall, therapeutic angiogenesis has accumulated a “critical mass” of evidence and approaches that would allow its application in practice within the next 10–15 years expanding the capabilities of treatment. However, possibility to shift from initially used non-option or critical patients may lead to better results in clinical trials, especially in gene therapy, where numerous failures put the whole concept under question several years ago. Development of cell therapy was accompanied by a large framework of regulatory, legal, ethical and industrial work to ensure safety and patients’ benefit. Number of clinical trials is growing every year and fortunately no serious evidence for adverse events or other risks for subjects’ health and well-being was found up-to-date.
\nTherapeutic angiogenesis has become one of the pioneer methods in translational medicine and its full potential is yet to be unleashed especially in the field of ex vivo modification and tissue-engineered approaches to increase efficacy and ensure safety.
Study and publication was supported by a grant from Russian Scientific Foundation (RSF) №16-45-03007.
Please provide publisher name and location for ref. 14.
Please provide page number for reference 49.
Please complete and update the reference given here (preferably with a DOI if the publication data are not known): [101].
Lipedema is a chronic underrecognized adipose tissue (AT) disorder distinguished by the symmetrical accumulation of painful fat in the lower body, predominantly in the thighs. The clinical presentation of lipedema resembles that of obesity, lymphedema, and other AT disorders, so it is often misdiagnosed and mistreated [1, 2, 3, 4]. Lipedema is diagnosed by a thorough physical examination in conjunction with the patient’s family and medical histories. Healthcare providers identify lipedema through the following criteria: bilateral and symmetrical distribution of subcutaneous fat predominantly in the legs that excludes the hands or feet, minimal pitting edema and a negative Stemmer’s sign which can indicate edema followed by a set of detailed criteria that characterize regionalization of fat accumulation and pain, time of change in fat distribution, and diet resistance to discern the type and stage of the patient.
There are five different types of lipedema, which are based upon the regions of prominent fat deposition. Type 1: the fat builds up in the buttocks and hip; Type 2: the fat spreads from the buttocks to the knees with fat folds around the inside of the knee; Type 3: the fat extends to the hips and ankles, the feet are not affected; Type 4: the fat is increased in the upper arms sparing the wrist and Type 5: the fat accumulates in the lower legs only [2, 5, 6]. Patients may present with more than one type depending on the progression of the disorder. Additionally, patients present at three different stages, depending on the severity of fat accumulation and the onset of other symptoms [2, 5, 6, 7]. Stage 1: the skin is smooth with small fat lobules; Stage 2: the skin has indentations with pearl-sized fat nodules and Stage 3: the skin has large extrusions with overhanging fat causing tissue deformities. Lymphedema may also develop collaterally at any stage of the disorder but does not alone qualify a case of lipedema [2]. Unlike many AT disorders, lipedema is largely irresponsive to lifestyle interventions such as diet and exercise, but liposuction and decongestive therapy are effective treatment options [1]. While neither are curative, liposuction is widely accepted as the better treatment option for its ability to provide long-term improvement to appearances, functionality, mobility and bruising while reducing edema, spontaneous pain, sensitivity to pressure. Combined decongestive therapy (CDT) such as pre- or post-operative lymphatic drainage or use of compression garments in recovery weeks may be conducted in support of the procedure [2, 4].
Lipedema predominantly affects females and often manifests during time of hormone fluctuations, during puberty, childbirth, or menopause [7, 8], indicating that estrogen and estrogen signaling play a role in the pathogenesis of lipedema via direct impacts on adipocytes and immune cells, and/or secondary effects on the brain control centers [9, 10]. However, the exact mechanism(s) of action remain unclear [11, 12]. Although lipedema is a common disease (11% of women worldwide), no data are yet available to demonstrate the prevalence of lipedema in pre- and post-menopausal or pregnant women. In addition, cases of lipedema in males are very rare; however, men who develop lipedema tend to have high levels of estrogen but low testosterone levels [2, 5, 6]. Understanding the mechanisms of the life-long transitions of estrogen levels and interactions with AT will define the pathogenesis of lipedema more thoroughly while identifying novel diagnostic and treatment options.
This review will describe the potential role of estrogen in the development of lipedema. The effect(s) of estrogens on the immune system will be described, the association of estrogen signaling on tissue adipogenesis and inflammation will be explored and the application of estrogen as a potential therapy in preventing the progression of this disease will be discussed.
Estrogens are hormones that regulate adipose tissue metabolism by controlling food intake, energy expenditure and body distribution. Estrogens have widespread effects on several organs around the body and therefore play a role in a variety of physiological functions and disorders. Estrogens can act on receptors in both the cytoplasm and the plasma membrane to mediate protein expression involving cell proliferation and metabolism [12]. Estrogens are present in three forms: estrone (E1), estradiol (E2), and estriol (E3). Estradiol is the most extensively studied, as it plays key roles in reproductive phase functioning and a large variety of chronic disorders. There are three receptors that have distinct presences and functions around the body. Alterations in estrogen activity or the absence of estrogen receptors (ER) results in the accumulation of subcutaneous adipose tissue (SAT), a phenomenon observed in lipedema patients [5, 9, 13, 14]. Szél et al. hypothesized that alteration in ERs is involved in the regulation of appetite and weight gain which might explain why lipedema patients accumulate fat and have difficulty losing it with diet and exercise [10]. Furthermore, Yi et al. showed that estrogen regulates the expression of leptin, a hormone that controls hunger and body weight, in adipocytes via ERs [15] supporting the hypothesis that lipedema is a hormonal disease.
Estrogen exerts its function through the estrogen receptor alpha (ERα) and beta (ERβ). Both ERα and ERβ receptors appear in significantly high concentrations in SAT of premenopausal women, as signaling from estrogens mediates adipose deposition throughout the body [9, 16]. However, ERα expression is reduced in the SAT of clinically obese females and postmenopausal women treated with estradiol compared to their normal-weight counterparts [14, 17, 18]. Interestingly, Erβ, which serves an antagonistic role on ERα-mediated gene expression, is highly expressed in postmenopausal women in comparison to premenopausal women [19]. Such findings raise the question of whether a correlation of the concentrations of estrogen receptors in adipose tissue could elucidate a similar relationship between estrogen receptor concentrations in lipedema AT. Additionally, a study conducted by Gavin et al. discovered described that the concentration of ERα is decreased and ERβ concentration is increased in the lower extremities of overweight patients, associating the variable concentrations to sexual dimorphisms in regionalized fat deposition for individuals [20]. As discussed earlier, fat accumulates in the lower extremities of lipedema patients, implying a potential role of ER in its pathogenesis. Furthermore, Dieudonné and colleagues evaluated the expression of ERs in preadipocytes and adipocytes in a cohort of lean subjects and determined that males and females statistically share similar levels of both ERα and ERβ within intraabdominal AT (IAT) and SAT [14]. Females have slightly higher concentrations of ERα and ERβ globally than males. However, when induced with estradiol, expression of ERα in the SAT in females increased significantly more than in IAT. In these same conditions, the SAT in females have a significantly increased expression of ERβ while all other levels of ERβ (IAT in females, SAT and IAT in males) remained the same. Cases of increased regionalized lipid accumulation are closely correlated to estrogen deficiency [21, 22, 23, 24]. In contrast, in an estrogen-sufficient state, excess fat is stored in the gluteal-femoral region, rather than the abdominal region. One mechanism has been postulated as a factor in this association is the acute administration of estrogens to postmenopausal women which reduced basal lipolysis in SAT, particularly in the femoral region, further supporting a role for estrogens in regional fat deposition in lipedema patients [25].
The third estrogen receptor, G protein-coupled estrogen receptor (GPER) is expressed on the membrane at lower concentrations in adipose tissue but nonetheless, with several important effects. GPER has been widely studied in regulation of body weight, inflammation, insulin sensitivity, and metabolic dysfunction [26, 27, 28, 29]. Several studies demonstrated that mice lacking GPER demonstrate an increase in adiposity (mass and adipocyte size) and decrease in energy expenditure compared to their wild type mice [29, 30, 31]. Studies have also shown that the lack of GPER or ERα expression in mice show similar characteristic of metabolic syndrome such as inflammation, obesity, glucose intolerance and insulin resistance [26, 31, 32, 33, 34]. Although the actions of estrogens on GPER have not yet been fully elucidated, examining the crosstalk between ERs and estrogen will help understand their function in the development of lipedema.
Estrogens have been shown to play a role in gender and regional adiposity. Several studies revealed that women have ~10% more early stage preadipocytes in abdominal SAT and ~35% more in femoral SAT [35, 36]. However, only ERα is expressed in preadipocytes, suggesting a role for estrogen in adipogenesis that is not mediated by the antagonistic mechanisms of ERα and ERβ [16]. Lacasa et al. found the mechanisms involved by which estrogen stimulates preadipocyte proliferation, supporting a role of estrogen in adipogenesis [13, 37]. However, Eaton et al. postulated that local adipocyte-produced estrogen may play a role in preventing preadipocyte differentiation based on data from two studies where treatment of preadipocytes with estrogen, both in vitro and in vivo, inhibited adipogenesis and lipogenic gene expression [13, 38]. The distribution of preadipocytes and adipocytes along with the expression of estrogen receptors on differentiated adipocytes could play a role in the pathogenesis of lipedema, as regionalized and sexually distinct adipocyte hypertrophy is one of the central defining characteristics of the disorder.
Activation of ERα, ERβ, and GPER on adipocytes elicit an intranuclear response, causing up or down-regulation in the expression and activity of proteins such as leptin and lipoprotein lipase (LPL), which are involved in lipid regulation in the body [39, 40]. Through this regulation of protein expression, estrogen partially mediates weight control and lipogenesis-lipolysis mechanisms. Moreover, several studies have shown that estrogen treatment altered the expression of several genes involved in lipogenesis. A study conducted by Homma et al. revealed a negatively controlled estrogen response element in the LPL gene, indicating that estrogen decreases activity of LPL, a protein that regulates lipid uptake by adipocytes and leads to lipogenesis, which inhibits adipose deposition [41]. Another study has shown that estrogen stimulates the expression of leptin in human breast tissue [42]; thus, estrogen might play an important in the regulation of adipose tissue. We have shown that leptin gene expression is increased in adipocytes differentiated in vitro from adipose-derived stem cells obtained from obese lipedema patients compared to the same cells from healthy controls [43]; however, the effect of estrogen on the expression of leptin in lipedema has yet to be determined. Additionally, ERβ has been shown to be a negative regulator of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor highly expressed in AT and controls the expression of LPL, glucose transporter type 4 (Glut 4) and leptin; thus, a decrease in ERβ expression increases adipogenesis which is detected in lipedema SAT [43]. However, further studies will be needed to study the correlation between the loss of ERs expression and the increase adiposity in AT disorders.
Estrogen exerts regulatory effects on the immune system through ER-dependent and independent pathways [44], which can be both positive and negative depending on a wide array of factors such as the level of estrogen, expression of ERs, cell types and the environment [45]. Lipedema AT is characterized by hypertrophic adipocytes and activated immune cells such as macrophages and mast cells [46, 47, 48]; thus, direct, and indirect cellular interaction through auto- and paracrine secretions of inflammatory cytokines via the ER signal transduction pathway have an immense impact on the tissue function [7, 19, 35]. Several studies have shown that a decrease in estrogen levels results in increased expression of pro-inflammatory cytokines, including interleukins (IL)-6, IL1-β and Tumor Necrosis Factor-alpha (TNF-α) as is the case with women undergoing menopause or oophorectomy [49]. On the other hand, in the case of pregnant women or in women taking ectopic estrogens, suppressed immune responses are observed [48]. Hence, as estrogen levels fluctuate in lipedema patients during their lifetime, the inflammatory signals in the tissue may as well. This correlation between estrogen levels and onset of inflammation could provide insight into the pathophysiology of lipedema-associated inflammation.
Estrogen is widely known as a central regulator of fat metabolism and regional deposition. In premenopausal women, estrogen is synthesized in the ovaries during menstruation [19]; however, it is depleted as they age. In adipose tissue, androgens are aromatized into estrogens to restore hormonal levels and prevent the progression of hormonal-related diseases [17, 19, 50]. One study found increased aromatase activity in a group of obese individuals, supporting a correlation between this shift of hormone production and metabolic disease [51]. However, estrogen deficiency or depletion, such as in the case of ovariectomy, polycystic ovary syndrome (PCOS), or the lack of a functional aromatase gene, causes weight gain which is associated with comorbidity, cardiovascular disease, and other diseases; thus, hormone replacement therapy (HRT) was shown to be an effective treatment [52, 53, 54, 55, 56, 57]. In the context of AT, administration of exogenous estradiol to premenopausal women decreases LPL activity in AT of the lower extremities, which are primarily affected in lipedema [58]. However, another study conducted by Lindberg et al. found that the treatment of postmenopausal women with oral ethinyl estradiol (50 μg/day) for three weeks increased adipose tissue LPL activity in femoral adipocytes [59]. Other studies expand on this, finding that estrogen treatment of adipocytes decreased the expression of genes related to adipogenesis and lipogenesis such as PPAR-γ and LPL [19, 38, 58]. Furthermore, administering estrogen resulted in a significant decrease in LPL activity in adipose tissue [52]. Similarly, Pederson et al. discovered that estrogen treatment almost doubled insulin binding affinity in rat adipocytes. Control rats had 11% weight gain in 7 days whereas estrogen treated rats gained only 4% in the same period. Adipocytes were significantly larger in control rats compared to adipocytes from estrogen substituted rats. Interactions of estrogens with androgens to mediate these processes were also discovered, with two studies observing the effects of HRT that further substantiate an association between androgens and weight gain [54, 60]. Davis et al. reported that administering androgens with estrogens in hormone replacement therapy seemed to antagonize or reduce the effects of estrogens on fat deposition and weight loss. Likewise, Gamberini et al. reported administration of antiandrogens with the typical estrogen dosage results in more efficient weight loss. While the effects of androgens in lipedema cases have been underdefined in this literature review, the pathophysiological effect of androgen therapy implies a treatment option for cases of lipedema. Clinical research has also found that women receiving estrogen HRT have relatively increased protection from metabolic syndrome and decreased AT deposition in the intra-abdominal region [13, 61, 62, 63, 64]. Additionally, as mentioned above, post-menopausal clinical subjects developed high levels of inflammatory cytokines had associated decreases in such levels following estrogen treatments [13]. All these data confirm that the physiological impact of estrogen is altered as females passes through reproductive benchmarks, and thus estrogen may be a potential treatment of Lipedema patients.
Furthermore, it has been proposed that activation of ERα can induce the browning of white adipocytes, referred to as beiging, through induction of lipolysis mediated by adipose tissue triglyceride lipase [65]. It is known that premenopausal women have more brown adipose tissue (BAT) and are more sensitive to brown adipose tissue activation than men or postmenopausal women. Selective activation of ERα by pyrazole triol (selective ERα agonist) increased markers of beiging in vitro [65]. The results of this study indicated that selective activation of ERα in adipocytes can induce beiging through the induction of adenosine monophosphate-activated protein kinase (AMPK) mediated lipolysis providing free fatty acids as an energy source to activate Uncoupling protein (UCP)-1 [66]. Another study conducted Yepuru et al. demonstrated that activation of ERβ increases mitochondrial function and energy expenditure; thus, ERβ ligands have anti-obesity and antimetabolic disease effects [67] and might be more beneficial than estradiol treatment which unselectively activates both ERs. In vitro and in vivo studies have suggested that selective ERβ ligand reduces the expression of genes associated with white adipose tissue and promote the expression of genes associated with brown adipose tissue. This ligand additionally increases the mitochondrial oxygen consumption without an increase in physical activity [68]. Additional research is needed to gain insight into whether selectively activating of one estrogen receptor over another confers more benefits than activating both unselectively. Given these results on the selective activation of estrogen receptors, there is an increased effort to characterize specific molecular pathways to induce white adipose tissue browning; thus, presenting another potential treatment for lipedema patients.
Lipedema is a severe chronic adipose tissue disorder that affects women worldwide. Although the pathophysiology of the disease has not been fully elucidated, several lines of evidence have suggested estrogen dysfunction may be central to the development of lipedema. The loss of estrogen can additionally induce cardiovascular disease and create an insulin resistant dyslipidemia state that can have long term implications on the metabolic profile of a patient. Thus, studying the role played by estrogen in the processes are involved in the pathogenesis, AT inflammation, fibrosis, and angiogenesis, will provide researchers insights into the mechanism involved in the development of the disease and will help direct future study on hormonal therapy as a form of treatment for lipedema. Through these efforts, the correlation revealed between hormones and adipogenesis in AT will lead to evaluate lipedema as a hormonal disease.
This work was funded by a grant from the Lipedema Foundation.
The authors declare no conflict of interest.
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\n\n"In developing countries until now, advancement in science has been very limited, because insufficient economic resources are dedicated to science and education. These limitations are more marked when the scientists are women. In order to develop science in the poorest countries and decrease the gender gap that exists in scientific fields, Open Access networks like IntechOpen are essential. Free access to scientific research could contribute to ameliorating difficult life conditions and breaking down barriers." Marquidia Pacheco, National Institute for Nuclear Research (ININ), Mexico
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