FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2066040738> ?p ?o ?g. }

• W2066040738 endingPage "1808" @default.
• W2066040738 startingPage "1795" @default.
• W2066040738 abstract "HomeCirculationVol. 125, No. 14Epithelial-to-Mesenchymal and Endothelial-to-Mesenchymal Transition Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBEpithelial-to-Mesenchymal and Endothelial-to-Mesenchymal TransitionFrom Cardiovascular Development to Disease Jason C. Kovacic, MD, PhD, Nadia Mercader, PhD, Miguel Torres, PhD, Manfred Boehm, MD and Valentin Fuster, MD, PhD Jason C. KovacicJason C. Kovacic From the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY (J.C.K., V.F.); the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (N.M., M.T., V.F.); Center of Molecular Medicine, National Heart, Lung and Blood Institute, Bethesda, MD (M.B.); Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Mount Sinai School of Medicine, New York, NY (V.F.). Search for more papers by this author , Nadia MercaderNadia Mercader From the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY (J.C.K., V.F.); the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (N.M., M.T., V.F.); Center of Molecular Medicine, National Heart, Lung and Blood Institute, Bethesda, MD (M.B.); Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Mount Sinai School of Medicine, New York, NY (V.F.). Search for more papers by this author , Miguel TorresMiguel Torres From the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY (J.C.K., V.F.); the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (N.M., M.T., V.F.); Center of Molecular Medicine, National Heart, Lung and Blood Institute, Bethesda, MD (M.B.); Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Mount Sinai School of Medicine, New York, NY (V.F.). Search for more papers by this author , Manfred BoehmManfred Boehm From the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY (J.C.K., V.F.); the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (N.M., M.T., V.F.); Center of Molecular Medicine, National Heart, Lung and Blood Institute, Bethesda, MD (M.B.); Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Mount Sinai School of Medicine, New York, NY (V.F.). Search for more papers by this author and Valentin FusterValentin Fuster From the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY (J.C.K., V.F.); the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (N.M., M.T., V.F.); Center of Molecular Medicine, National Heart, Lung and Blood Institute, Bethesda, MD (M.B.); Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Mount Sinai School of Medicine, New York, NY (V.F.). Search for more papers by this author Originally published10 Apr 2012https://doi.org/10.1161/CIRCULATIONAHA.111.040352Circulation. 2012;125:1795–1808IntroductionCellular switching from an epithelial-to-mesenchymal phenotype, and conversely from a mesenchymal-to-epithelial phenotype, are important biological programs that are operative from conception to death in mammalian organisms. Indeed, the capacity of cells to switch between these states has been fundamental to the generation of complex body patterns throughout evolution. Phenotypic switching from an epithelial to mesenchymal cell, termed epithelial-to-mesenchymal transition (EMT), was a paradigm that evolved from numerous observations on early embryonic development, the foundations of which date back to the 1920s and the pioneering work of Johannes Holtfreter on embryo formation and differentiation.1,2 By the late 1960s, seminal chick embryo studies by Elizabeth Hay3 led to the first formal description that epithelial cells can undergo a dramatic phenotypic transformation and give rise to embryonic mesoderm.4 Subsequent studies have revealed that this process is reversible (mesenchymal-to-epithelial transition [MET]), and gradually the term ‘transition” has come to replace ‘transformation.”Given that EMT/MET was initially identified and described by developmental biologists, it is perhaps not surprising that these processes are best understood during embryonic implantation and development. As explored in this review, it is now known that successive waves of cellular transition, from an epithelial to mesenchymal and then back to an epithelial state, are required for normal embryonic patterning and organ formation. In addition, numerous studies that span a broad spectrum of physiological and pathological conditions have expanded our knowledge of EMT/MET and now provide evidence for the important role played by these processes in various adult conditions including fibrosis, wound repair, inflammation, and malignancy. Indeed, our conceptual framework now also encompasses several variations and subcategories of cellular phenotypic switching, including endothelial-to-mesenchymal transition (EndMT).In this review, epithelial, endothelial, and mesenchymal phenotypic cellular switching will be explored in the cardiovascular system, spanning cardiovascular development through to adult end organ disease. Key areas of recent scientific progress will be examined, including recent developmental and pathological insights, which potentially may lead to novel therapeutic opportunities.EMT: A Key Role in Early DevelopmentWithin days of conception and during very early embryonic implantation, the process of EMT is already operative. Typically at the blastocyst stage, after initial adherence to the uterine lining (decidua), the outer trophoblast sends forward columns of epithelial cells to penetrate the uterine wall.5 At the leading edge of these embryonic cellular columns, epithelial trophoblast cells undergo EMT and invade the underlying maternal decidual interstitum and vessels. These invading embryonic cells ultimately go on to become mesenchymal placental giant cells, participating in the remodeling of the maternal uterine vasculature and securing a functional placental blood supply.5 This embryonic execution of the EMT program establishes cellular phenotypic switching as a key biological paradigm and, interestingly, sets an early precedent for the vascular involvement of this process.Soon after these events, EMT plays a pivotal role in germ layer specification (ectoderm, mesoderm, endoderm). Epithelial cells from the primitive epiblast layer migrate to the midline and undergo EMT to give rise to mesoderm and endoderm.6 This process is highly ordered in time and space and generates pools of primitive stem/progenitor cells at precise anatomic locations within the embryo, which constitute the primordia of the developing organs. For example, lateral plate mesoderm gives rise to the heart and hematopoietic cells, the paraxial mesoderm to the musculo-skeletal system, and the intermediate mesoderm to the urogenital tract. These events, occurring in tissues that have not previously undergone cellular phenotypic switching, are termed primary EMT (Figure 1).Download figureDownload PowerPointFigure 1. Organ formation occurs via EMT/MET. Embryonic cells from the epiblast layer (a single layer of epithelial cells) give rise to mesodermal cells via primary EMT. Definitive organ formation then ensues via secondary EMT and successive rounds of EMT/MET. Differing regions of the mesodermal layer give rise to differing organs/structures: The heart, circulatory system, and hematopoietic cells arise from lateral plate mesoderm, the urogenital system from intermediate mesoderm, the axial skeleton and skeletal muscle from paraxial mesoderm, and the primitive notochord (which becomes the nucleus pulposus of intervertebral discs in the adult human) from the axial (midline) mesoderm. This Figure depicts cardiac formation. EMT-MET is also involved with endoderm and ectoderm tissue/organ formation. EMT indicates epithelial-to-mesenchymal transition; MET, mesenchymal-to-epithelial transition; TGF-B, transforming growth factor β; BMPs, bone morphogenic proteins; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; and TB4, thymosin β4.Having established these primitive mesodermal populations, successive waves of EMT/MET then typically occur before final organ formation. In the case of the heart, this can involve recurrent waves of EMT/MET before the heart begins to assume a recognizable 4-chambered form (see section ‘Early Cardiac Formation”). For other organs, such as the kidney, successive waves of EMT/MET are required to ultimately give rise to epithelial structures such as nephrons and nephric ducts.7Genetic, Molecular, and Cellular Basis of EMT/METAt the core of EMT/MET, fundamental molecular and architectural rearrangements occur to bring about the dramatic cellular changes necessary to switch phenotypes. Underpinning this is a complex network of gene activation and repression programs that are required for the initiation, execution, and maintenance of EMT or MET (Figure 2).Download figureDownload PowerPointFigure 2. Key aspects of the molecular and cellular changes that occur with EMT. BM indicates basement membrane; MMPs, matrix metalloproteinases; EMT, epithelial-to-mesenchymal transition; αSMA, α–smooth muscle actin; DDR2, discoidin domain receptor 2; and FSP1, fibroblast-specific protein 1.At the cellular level, gross changes in polarity, morphology, functionality, and cell–cell interactions are requisite steps. Epithelial cells are arranged on a basement membrane, exhibiting apico-basal polarity and abundant expression of intercellular adhesion complexes such as E-Cadherin and integrins. In order to adopt a mesenchymal phenotype, these cells must lose cell adhesion by E-Cadherin downregulation and degradation.8,9 Other epithelial proteins such as zonula occludens, cytokeratin and desmoplakin must also be repressed.8–11 Transitioning cells then progressively lose polarity while eroding the basement membrane by matrix metalloproteinase production (matrix metalloproteinases 2, 3, and 9).12,13 Cytoskeletal changes mediated by Rho GTPases induce apical constriction and further structural rearrangements to permit passage through the degraded basement membrane, culminating in delamination from the epithelial layer.14 Completing the transition, cells activate the expression of additional mesenchymal genes and proteins, such as α–smooth muscle actin (αSMA), smooth muscle protein 22α, collagen I and III, vimentin, fibronectin, or fibroblast-specific protein 1 (FSP1; also known as S100A4).8,15–17Orchestrating these processes, the most widely described regulator of EMT/MET is the transforming growth factor β (TGFβ) superfamily of signaling molecules (TGFβ, Nodal, bone morphogenic proteins [BMPs], and growth and differentiation factors).18–21 Downstream of the receptors for the various TGFβ superfamily members, the Smad family of signal transducers is also of key importance, and in particular Smad2 and Smad3 appear to control EMT program activation.18 In turn, TGFβ stimulation with Smad activation leads to transcription of Snail 1 and 2 (the latter formerly known as Slug) and Twist, further triggering a cascade of signaling pathways that culminate in EMT.22 Snail 1 is considered a key organizer of EMT, with one of its pivotal functions being to downregulate E-Cadherin transcription.22,23 The downregulation of E-Cadherin and other tight junction components9 directly facilitates the loss of epithelial intercellular adhesions and cellular delamination from the epithelial layer. The TGFβ signaling network is a key mediator of early-development EMT, and although other non-EMT effects are also operative, the genetic mutation of any number of these TGFβ family members often results in a nonviable embryo with major tissue, cardiovascular, or other organ specification defects.24–28 Importantly, not all members of the TGFβ superfamily stimulate EMT, with BMP-7 antagonizing TGFβ signaling and inhibiting EndMT in cardiac (see section ‘EndMT Contributes to Cardiac Fibrosis in the Adult Heart”)19 and renal20 fibrosis models.Several other signaling pathways also modulate EMT and MET, such as Notch and Wnt. For example, the canonical Wnt signaling pathway is crucial for events in early embryonic development, with chick embryos deficient in Wnt unable to properly form the ectoderm, mesoderm, and endodermal layers.29 The Notch pathway is an evolutionarily conserved and complex signaling network that also plays an important role in embryonic development. Although not generally considered a master regulator of EMT, at least in certain scenarios it appears to act upstream of TGFβ signaling.30 As a whole, the cellular rearrangements and changes that occur with EMT are extensive, and it is estimated that EMT in human cells changes the expression of ≈4000 genes, representing ≈10% of the entire genome.31 Additional signaling pathways are discussed below as relevant to cardiovascular development and disease, and interested readers are referred to any of the several excellent reviews on the molecular basis of EMT.32–34Classification and Types of EMTEpithelial-to-mesenchymal transition is classified into 3 types depending on its biological (or pathological) role and the time window in which it occurs. The embryonic and developmental EMT programs described above are classified as type-1 EMT, being distinct in that they do not generally cause fibrosis or give rise to mesenchymal cells with an invasive phenotype. As shown in Figure 3, the remaining types (2 and 3) are operative after birth and are concerned with fibrosis and malignant cellular transformation respectively. Type-2 EMT is extensively described in the literature, and it appears that chronic inflammation may be the sovereign inciting injury that triggers this form of EMT and sets the stage for end organ disease. Although the hypothesis is not without controversy,35,36 evidence exists to support type-2 EMT in numerous adult conditions, including those affecting the kidney,17,20,37 liver,38 skin,39 intestines,40 lungs,41 eyes,42 and heart (the latter will be considered separately in the section ‘EndMT Contributes to Cardiac Fibrosis in a Adult Heart”).19 Type-3 EMT is an important step in malignant cell transformation. Of particular relevance with respect to carcinoma (epithelial cell tumors), EMT is proposed as a critical mechanism for the acquisition of malignant characteristics, with loss of E-Cadherin expression facilitating the delamination and metastasis of transformed epithelial cells.34,43Download figureDownload PowerPointFigure 3. Classification of EMT. Type-1 EMT is highly regulated and is associated with embryonic implantation and organ formation. Type-1 EMT may be subclassified into primary (cells giving rise to EMT for the first time), secondary, and tertiary, with these latter forms involved in the successive waves of EMT-MET leading to definitive organ formation. Type-2 EMT is associated with inflammation and fibrosis and is now increasingly recognized in adult pathological conditions. Type-3 EMT is involved with malignant cell transformation, including the acquisition of invasive metastatic cellular properties. As distinct from type-1, neither type-2 nor type-3 EMT adhere to any higher-order program of spatial or temporal restriction. EMT indicates epithelial-to-mesenchymal transition; MET, mesenchymal-to-epithelial transition.A further aspect of this classification system requiring clarification is the place of EndMT. The endothelium is a specialized form of squamous epithelial tissue, and as such, EndMT is a subcategory of EMT. Accordingly, EndMT may be observed in each of the 3 categories of EMT. For example, the endothelium gives rise to hematopoietic cells during embryonic development (type-1 EMT),44 and to both fibrosis and malignancy in the adult (types-2 and -3 EMT, respectively).19,45EMT During Cardiac Development: Valves, Cushions, Neural Crest, and Epicardium-Derived CellsEarly Cardiac FormationThe heart forms via a remarkable series of sequential waves of EMT/MET. As the definitive germ layers emerge in the developing embryo, cardiac progenitors are among the first epiblast cells to undergo EMT and to migrate out from the primitive streak.46,47 This population of mesenchymal cardiac precursors migrates bilaterally within the lateral plate toward the anterior pole of the embryo47–49 to coalesce in mammals into an anterior cardiac crescent.47 The formation of the celomic cavity divides the lateral plate to give rise to the somatic and splanchnic mesodermal layers. Within the splanchnic layer, primitive cardiac progenitor cells organize into a bilayered epithelium via MET.50 Next, either via another round of EMT/MET involving these mesodermal cardiac progenitor cells or from a separate cell population, the endocardial cells that will line the cardiac structures are formed.51–53 The primitive heart tube soon emerges by folding and remodeling of the cardiac crescent cells. Genetic and direct labeling of cardiac precursor cells at various stages of heart tube development has shown that the primary heart tube only contains the precursors of the left ventricle and that the remaining chambers are formed by the progressive infiltration and incorporation of new cardiac precursors into the outflow and inflow poles of the heart tube.54–56 The area of the cardiac crescent that gives rise to the initial heart tube is named the primary heart field whereas the area that remains behind in the pharyngeal region that is added later is called the secondary heart field. Primary and secondary heart field precursors occupy adjacent areas in the cardiac crescent but differ in the mechanism by which they are added to the heart tube (folding versus migration) and in the timing of addition. At the current time, the role of EMT in the migration and incorporation of second heart field precursors remains under investigation.EndMT Contributes to Valve Formation and Heart SeptationSoon after the primitive heart tube appears, endothelial cells from the region of the forming atrioventricular (A-V) canal and of the outflow tract (OFT) region undergo another round of EMT, or more specifically EndMT because the cells undergoing phenotypic switching are endothelial. At this time, the endocardium and the myocardium are separated by a thick acellular matrix termed the cardiac jelly. As the cardiac chambers start to form, the cardiac jelly gets thicker in the A-V canal and OFT regions, where endothelium-derived mesenchymal cells invade the adjacent cardiac jelly to form endocardial cushion tissue.57 The OFT cushions are the precursors of the semilunar valves whereas the A-V cushions give rise to the A-V septum, the membranous part of the ventricular septum and the mitral and tricuspid valves.58 The extent to which EndMT contributes to these 2 cushion areas differs significantly, and although most of the A-V cushion mesenchyme derives from EndMT,57 most of the OFT cushion derives from pharyngeal mesodermal cells. Subsequently, both cushions receive further specific mesenchymal cellular contributions involving EMT. The OFT region receives an important third mesenchymal population arising from the neural crest, which delaminates by EMT from the neural tube.59 This neural crest–derived population is essential for OFT septation into the aortic and pulmonary trunks; however, it represents a transient population that does not contribute significantly to the definitive heart structures. In the region of the A-V canal, a third mesenchymal population derives from EMT of the epicardium.60,61EMT and the EpicardiumIn parallel with endocardial EndMT and cushion formation, the outermost epicardial layer of the heart is also coming into existence.62 Like the primitive early cardiac progenitor cells, epicardial progenitor cells also arise from the splanchnic mesoderm (likely also via MET). Initially, the cells destined to form the epicardium assemble to create a transitory body of cells termed the proepicardial organ, consisting of an accumulation of pericardial progenitor cells lying adjacent to the sinus venosus (the venous pole of the heart; Figure 4A). These proepicardial cells migrate, or in some species float freely within the pericardial cavity, and attach to the myocardial surface.63–67 There, they proliferate and flatten to cover the embryonic heart as the epicardial sheet. Concomitantly, some epicardial cells undergo EMT and generate a mesenchymal population of epicardium-derived cells (EPDCs). Although a population of EPDCs remain to occupy the extracellular matrix–rich region between the epicardium and myocardium named the subepicardial space, some migrate further to invade the myocardium.Download figureDownload PowerPointFigure 4. Origin and fate of EPDCs. A, Messenger RNA in situ hybridization for tbx18 on zebrafish sagittal heart sections marking epicardial cells (blue staining). Additional immunostaining against myosin heavy chain was performed to identify myocardium (brown staining) and is shown in the lower panels (e–g). These panels show the progressive developmental sequence of epicardial formation in zebrafish, with vertically matched panels taken from the same developmental stage (a, 2 days postfertilization [dpf]; b and e, 3 dpf; c and f, 4 dpf; and d and g, 5 dpf). PE indicates proepicardium; Epi, epicardium; HT, heart tube; V, ventricle; and A, atrium. B, Epicardial EMT during zebrafish regeneration. a and c, Anti-GFP immunohistochemistry on adult zebrafish heart sections from the transgenic ET-27 line, expressing GFP constitutively in all epicardial cells (brown staining). b and d, In situ hybridization on sections of cryoinjured Tg(wt1b:GFP) zebrafish hearts, in which GFP is reactivated in the epicardium on damage (blue staining). Dorsal is to the top (a). The control heart reveals a single layer of GFP-positive cells on the ventricular surface. b, On cryoinjury, the epicardium thickens as a consequence of injury-induced EMT. c, Enlargement is 20× the scale of control heart. d, Enlargment is 20× the scale of injured heart. Images acquired at Centro Nacional de Investigaciones Cardiovasculares (Madrid, Spain) by the group of Nadia Mercader.The developmental cellular contributions of EPDCs are controversial and potentially species-dependent. An important contribution of EPDCs is made to the A-V canal cushion mesenchyme where EPDCs merge with endocardium-derived cells to form the mitral and tricuspid valves and cardiac septa.60,61,68 Interestingly, EPDCs do not colonize the OFT cushions, perhaps implying a specific role for these cells in the formation of the tricuspid and mitral but not the pulmonary and aortic valves. Epicardium-derived cells also play a role in coronary vascular formation. Studies in avian species, which included labeling the proepicardium with replication-deficient virus62,69 or the generation of quail-chick chimeras,60–62,70 indicated that EPDCs are the primary source of coronary endothelial cells, coronary vascular smooth muscle cells (cVSMCs) and cardiac fibroblasts. More recently, genetic fate mapping experiments have investigated the fate of EPDCs in the mouse. T-box transcription factor 18 (Tbx18) and Wilms tumor suppressor 1 (Wt1) are broadly expressed in the proepicardium and epicardium during development and represent appropriate markers to trace EPDCs.71–74 Using Cre-based technology, the fate of Tbx18+ and Wt1+ cells was analyzed,68,75 confirming that EPDCs differentiate into cVSMCs and cardiac fibroblasts. However, in mice, in contrast to the chick, no contribution to coronary endothelial cells was identified for Tbx18+-derived cells and only a minor contribution was found from Wt1+ cells. Very recently, Kikuchi et al have also demonstrated that in zebrafish, whereas EPDCs contribute to perivascular cells, they do not give rise to endothelial cell populations.76 Potentially, this discrepancy in the contribution of EPDCs to the endothelium in avian versus other species may be explained by species-specific differences or may reflect differing experimental approaches used to study EPDC fate. It is also possible that the initial observations performed in the chick were not correctly interpreted or that contamination by non-EPDC endothelial precursor cells migrating together with the proepicardium during grafting/labeling may have occurred.77,78Consistent with this, genetic evidence from the mouse supports the classic notion that the coronary endothelium derives from the sinus venosus.79 Using inducible vascular endothelial-cadherin-Cre mice to trace endothelial cell clones, it was determined that most coronary veins and arteries derive from sprouts arising at the sinus venosus, with a lesser proportion potentially arising from the endocardium. Importantly, no endothelial clones were linked to the proepicardium, suggesting that this structure does not contribute to endothelial progenitors, although it remains possible that epicardial cells may commit to the endothelial lineage at a later developmental stage, after colonization of the myocardial surface.Interestingly, analysis of Tbx18+ and Wt1+ epicardium-derived lineages also revealed an unexpected myocardial contribution. Thus, ≈4% of total cardiomyocytes were found to have arisen from Wt1+ cells, contributing mostly to the intraventricular septum (10%), atria (18%), and to a lesser extent the ventricular walls (7%).75 Similarly, the Tbx18+ lineage was found to contribute to cardiomyocytes in the ventricular septum and in scattered areas within the ventricular walls and atria.68 However, these findings remain under scrutiny because Tbx18 expression has been detected in maturing cardiomyocytes, potentially suggesting epicardium-independent Tbx18 activation in these cells.80 Furthermore, studies in zebrafish have also refuted the ability of EPDCs to give rise to cardiomyocytes.76Most recently, yet another contribution of EPDCs was revealed by Harvey and coworkers, who described a population of mesenchymal stem cell–like cells that occupy a perivascular adventitial niche in the adult mouse.81 Although the precise extent of their normal and pathological cellular contributions remains to be defined, these proepicardium/epicardium-derived stem cells exhibit transgerm layer potency in vitro and in vivo and appear distinct from previously described resident cardiac stem cell populations.In summary, it is clear that EMT-derived EPDCs support coronary artery development by supplying vascular pericytes and cVSMCs and that they make a major contribution to fibrous cardiac tissues/populations, including resident perivascular fibroblasts and the fibrous cardiac skeleton.60–62,68,69,75,77,78,82 Although the ability of EPDCs, other epicaridal cells, or both to give rise to cardiomyocytes and endothelium during development remains controversial, it is clear that the EMT and MET programs are of key importance during cardiac formation and for epicardial provisioning of specific cell populations.Signaling Pathways Governing EndMT/EMT During Cardiovascular DevelopmentSignaling via the TGFβ superfamily, as previously described in this review, is the major regulator of EMT during cardiac formation, including TGFβ2, TGFβ3, and BMP-2 and the downstream transcription factors Snail1 and Snail2.83 The precise role of these TGFβ isoforms differs between species, and at least in the chick TGFβ2 mediates EndMT via endothelial cell activation and separation whereas TGFβ3 mediates cell invasion into the extracellular matrix.84In addition to TGFβ, numerous other pathways modulate EMT during cardiac formation and development. Notch signaling is of particular significance during murine cardiac development, functioning to promote endocardial EndMT and with Notch deficient embryos displaying atrophic valve formation.85 Expanding our understanding of these pathways, Luna-Zurita et al86 recently showed that Notch1 is sufficient to activate a cell-autonomous promesenchymal gene-expression program in endocardial cells. Bone morphogenic protein 2 was found to drive endocardial EndMT and mesenchymal cell invasion into the cardiac jelly. Further, myocardial BMP-2 inactivation impaired Notch1 activity,86 suggesting a model in which the interplay between myocardial BMP-2 and endocardial Notch signaling restricts EndMT to prospective valve territory.86,87Endocardial EndMT is also dependent on receptor tyrosine kinase signaling via the phosphoinositide-3 kinase–phosphoinositide–dependent protein kinase 1–Akt/protein kinase B cascade, which is upstream of Snail. Genetic ablation of dependent protein kinase 1 in endothelial cells leads to embryonic lethality with abnormal vascular remodeling and a failure of endocardial cushion development because of defective EndMT.88 Gata4, an upstream regulator of an Erbb3-Erk pathway, is expressed in the endothelium and mesenchyme of the embryonic A-V valves and is also required for endocardial EndMT. Selective Gata4 inactivation in endothelium-derived cells results in a failure of EndMT and hypocellular endocardial cushions in animal models.89 This phenotype corresponds with that seen in humans, where heterozygous Gata4 mutation is associated with defects in the interatrial or interventricular septae.90,91 Endocardial expression of the protein tyrosine phosphatase SHP2, encoded by the gene PTPN11, also regulates EndMT and endocardial cushion formation. Gain of function PTPN11 mutations are responsible for a significant proportion of cases of Noonan syndrome and cause cardiac valve and septal defects by increasing Erk–mitogen-activated protein kinase activation, probably downstream of ErbB family–receptor tyrosine ki" @default.
• W2066040738 created "2016-06-24" @default.
• W2066040738 creator A5025138239 @default.
• W2066040738 creator A5030796085 @default.
• W2066040738 creator A5038241917 @default.
• W2066040738 creator A5074727212 @default.
• W2066040738 creator A5090194847 @default.
• W2066040738 date "2012-04-10" @default.
• W2066040738 modified "2023-10-14" @default.
• W2066040738 title "Epithelial-to-Mesenchymal and Endothelial-to-Mesenchymal Transition" @default.
• W2066040738 cites W143420532 @default.
• W2066040738 cites W1512724671 @default.
• W2066040738 cites W1557028690 @default.
• W2066040738 cites W1564866496 @default.
• W2066040738 cites W1765845624 @default.
• W2066040738 cites W1810772665 @default.
• W2066040738 cites W1908640189 @default.
• W2066040738 cites W1964081206 @default.
• W2066040738 cites W1965774206 @default.
• W2066040738 cites W1966202908 @default.
• W2066040738 cites W1966563415 @default.
• W2066040738 cites W1966619985 @default.
• W2066040738 cites W1967227370 @default.
• W2066040738 cites W1969109536 @default.
• W2066040738 cites W1975619441 @default.
• W2066040738 cites W1979437598 @default.
• W2066040738 cites W1979990833 @default.
• W2066040738 cites W1982670131 @default.
• W2066040738 cites W1983228128 @default.
• W2066040738 cites W1983581444 @default.
• W2066040738 cites W1984668226 @default.
• W2066040738 cites W1985301994 @default.
• W2066040738 cites W1985422522 @default.
• W2066040738 cites W1985938739 @default.
• W2066040738 cites W1988832870 @default.
• W2066040738 cites W1989457690 @default.
• W2066040738 cites W1992056163 @default.
• W2066040738 cites W1993345123 @default.
• W2066040738 cites W1993530806 @default.
• W2066040738 cites W1993913999 @default.
• W2066040738 cites W1994134406 @default.
• W2066040738 cites W1994761680 @default.
• W2066040738 cites W1995565212 @default.
• W2066040738 cites W1996337584 @default.
• W2066040738 cites W1998147947 @default.
• W2066040738 cites W1998500791 @default.
• W2066040738 cites W1999133914 @default.
• W2066040738 cites W2005224639 @default.
• W2066040738 cites W2006482057 @default.
• W2066040738 cites W2008555822 @default.
• W2066040738 cites W2008724145 @default.
• W2066040738 cites W2008747758 @default.
• W2066040738 cites W2010672807 @default.
• W2066040738 cites W2011071265 @default.
• W2066040738 cites W2011152223 @default.
• W2066040738 cites W2011378193 @default.
• W2066040738 cites W2012416932 @default.
• W2066040738 cites W2014346447 @default.
• W2066040738 cites W2019127826 @default.
• W2066040738 cites W2020559241 @default.
• W2066040738 cites W2020597782 @default.
• W2066040738 cites W2020964402 @default.
• W2066040738 cites W2021017423 @default.
• W2066040738 cites W2022287530 @default.
• W2066040738 cites W2024229160 @default.
• W2066040738 cites W2024971066 @default.
• W2066040738 cites W2025027128 @default.
• W2066040738 cites W2025425480 @default.
• W2066040738 cites W2026261647 @default.
• W2066040738 cites W2027080314 @default.
• W2066040738 cites W2030555256 @default.
• W2066040738 cites W2030699054 @default.
• W2066040738 cites W2031137884 @default.
• W2066040738 cites W2031547948 @default.
• W2066040738 cites W2032196758 @default.
• W2066040738 cites W2037749195 @default.
• W2066040738 cites W2039801978 @default.
• W2066040738 cites W2040548182 @default.
• W2066040738 cites W2042531263 @default.
• W2066040738 cites W2044737538 @default.
• W2066040738 cites W2046248667 @default.
• W2066040738 cites W2047311303 @default.
• W2066040738 cites W2054458721 @default.
• W2066040738 cites W2054749956 @default.
• W2066040738 cites W2056524045 @default.
• W2066040738 cites W2056794607 @default.
• W2066040738 cites W2058822152 @default.
• W2066040738 cites W2059128799 @default.
• W2066040738 cites W2059137671 @default.
• W2066040738 cites W2059372860 @default.
• W2066040738 cites W2060126259 @default.
• W2066040738 cites W2061476658 @default.
• W2066040738 cites W2063724508 @default.
• W2066040738 cites W2064308916 @default.
• W2066040738 cites W2066196435 @default.
• W2066040738 cites W2070772918 @default.
• W2066040738 cites W2071017667 @default.
• W2066040738 cites W2072162746 @default.

• next