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Joy Lincoln - One of the best experts on this subject based on the ideXlab platform.
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the Endocardium and heart valves
Cold Spring Harbor Perspectives in Biology, 2020Co-Authors: Joy LincolnAbstract:Endocardial cells are specialized endothelial cells that, during embryogenesis, form a lining on the inside of the developing heart, which is maintained throughout life. Endocardial cells are an essential source for several lineages of the cardiovascular system including coronary endothelium, endocardial cushion mesenchyme, cardiomyocytes, mural cells, fibroblasts, liver vasculature, adipocytes, and hematopoietic cells. Alterations in the differentiation programs that give rise to these lineages has detrimental effects, including premature lethality or significant structural malformations present at birth. Here, we will review the literature pertaining to the contribution of endocardial cells to valvular, and nonvalvular lineages and highlight critical pathways required for these processes. The lineage differentiation potential of embryonic, and possibly adult, endocardial cells has therapeutic potential in the regeneration of damaged cardiac tissue or treatment of cardiovascular diseases.
Charles Antzelevitch - One of the best experts on this subject based on the ideXlab platform.
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differences in the electrophysiological response of canine ventricular epicardium and Endocardium to ischemia role of the transient outward current
Circulation, 1993Co-Authors: Anton Lukas, Charles AntzelevitchAbstract:BACKGROUND Acute ischemia is known to produce more severe electrophysiological disturbances in canine ventricular epicardium than Endocardium, although the mechanism for the differential sensitivity is still unresolved. Recent studies have demonstrated the presence of a prominent transient outward current (Ito) in ventricular epicardium but not Endocardium. The present study was designed to test the hypothesis that the differential sensitivity of these two tissues to ischemia results, at least in part, from a more prominent Ito in epicardium than in Endocardium. METHODS AND RESULTS Isolated canine ventricular epicardial and endocardial tissues and myocytes were studied by standard microelectrode techniques. Simulated ischemia (hyperkalemia, hypoxia, and acidosis) abolished the action potential plateau and caused a 50% to 60% shortening of action potential duration in epicardium but only a 10% to 20% shortening in Endocardium. 4-Aminopyridine, an Ito inhibitor, restored the plateau in epicardium and reduced the dispersion of action potential duration between epicardium and Endocardium. Stimulation protocols that minimized the contribution of Ito, such as acceleration of the stimulation rate or introduction of early premature beats, produced a paradoxical prolongation of the epicardial response caused by restoration of the action potential dome. Thus, ischemia-induced dispersion of repolarization was greatly diminished at rapid rates and after premature beats. Similar results were obtained in tissues and myocytes obtained from the same myocardial layers, suggesting that the differential sensitivities of epicardium and Endocardium to ischemia are largely a result of inherent differences in cellular properties. CONCLUSIONS Our data suggest that the presence of a prominent Ito in epicardium but not Endocardium contributes importantly to the selective electrical depression of epicardium by simulated ischemia. The repolarizing influence of Ito serves to amplify the ischemia-induced changes in inward (ICa and INa) and outward (calcium-activated) currents. By facilitating loss of the dome in epicardium, Ito contributes to the development of a marked dispersion of repolarization between normal and ischemic epicardium and between epicardium and Endocardium, thereby providing the electrophysiological substrate for the genesis of reentrant arrhythmias.
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sodium channel block produces opposite electrophysiological effects in canine ventricular epicardium and Endocardium
Circulation Research, 1991Co-Authors: S C Krishnan, Charles AntzelevitchAbstract:Using microelectrode techniques we compared the effects of tetrodotoxin (TTX, 2-3 microM), DL-propranolol (1-3 micrograms/ml), and flecainide acetate (10-15 microM) on isolated canine ventricular epicardial (epicardium) and endocardial (Endocardium) tissues. Propranolol, TTX, and flecainide decreased Vmax and phase 0 amplitude in a use-dependent manner in both tissues. The effects of propranolol were slow to develop and wash out. TTX and propranolol always abbreviated action potential duration in Endocardium. Action potential duration was abbreviated by 23.8 +/- 5.6 msec after propranolol (1 microgram/ml, basic cycle length [BCL] = 1,000 msec) and 10.8 +/- 12.9 msec after TTX (2 microM, BCL = 1,000 msec). In epicardium, the reduction of phase 0 and 1 amplitudes led to a slowing of the second action potential upstroke and an increase in the amplitude of phase 2. This accentuation of the notch resulted in a paradoxical prolongation of the epicardial action potential. Action potential duration was prolonged 34.4 +/- 11.3 msec after 4 hours of exposure to propranolol (1 microgram/ml, BCL = 1,000 msec), 11.1 +/- 6.3 msec after 15 minutes of exposure to TTX (2 microM, BCL = 1,000 msec), and 19.9 +/- 8.2 msec after 25-45 minutes of exposure to flecainide (15 microM, BCL = 500 msec). With stronger sodium block, phase 1 terminated at more negative potentials, the second upstroke often failed to appear, and an all-or-none repolarization ensued causing a marked abbreviation of the epicardial action potential. In some epicardial preparations, we observed marked abbreviation at some sites but prolongation at other sites after sodium blockade with flecainide. The dispersion of repolarization was often attended by reentrant activity. The differential response of epicardium and Endocardium to sodium blockade was not observed when the preparations were pretreated with 4-aminopyridine or ryanodine, agents known to diminish the transient outward current and epicardial notch. Acceleration-induced prolongation of refractoriness was observed after sodium blockade in epicardium but not in Endocardium. Postrepolarization refractoriness also occurred in epicardium but not in Endocardium after TTX, propranolol, or flecainide exposure. The data indicate that propranolol, TTX, and flecainide, via their action to block sodium current, may exert opposite effects on action potential duration and refractoriness in cells spanning the ventricular wall. The presence of the transient outward current in epicardium but not in Endocardium appears to contribute importantly to these differences.(ABSTRACT TRUNCATED AT 400 WORDS)
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a subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle the m cell
Circulation Research, 1991Co-Authors: Serge Sicouri, Charles AntzelevitchAbstract:Recent studies have shown that canine ventricular epicardium and Endocardium differ with respect to electrophysiological characteristics and pharmacological responsiveness and that these differences are in large part due to the presence of a prominent transient outward current Ito and a spike-and-dome morphology of the action potential in epicardium but not Endocardium. In attempting to quantitate these differences and assess their gradation across the ventricular wall, we encountered a subpopulation of cells in the deep subepicardial layers with electrophysiological characteristics different from those of either epicardium or Endocardium. These cells, which we have termed M cells, display a spike-and-dome morphology typical of epicardium but a maximal rate of rise of the action potential upstroke that is considerably greater than that of either epicardium or Endocardium. Using the restitution of the amplitude of phase 1 of the action potential as a marker for the reactivation of Ito, we showed M cells to...
Bin Zhou - One of the best experts on this subject based on the ideXlab platform.
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genetic fate mapping defines the vascular potential of endocardial cells in the adult heart
Circulation Research, 2018Co-Authors: Juan Tang, Hui Zhang, Wenjuan Pu, Xiuzhen Huang, Lingjuan He, Libo Zhang, Yan Li, Wei Yu, Bin ZhouAbstract:Rationale: Endocardium is the major source of coronary endothelial cells (ECs) in the fetal and neonatal hearts. It remains unclear whether Endocardium in the adult stage is also the main origin of neovascularization after cardiac injury. Objective: To define the vascular potential of adult Endocardium in homeostasis and after cardiac injuries by fate-mapping studies. Methods and Results: We generate an inducible adult endocardial Cre line ( Npr3 [natriuretic peptide receptor C]- CreER ) and show that Npr3-CreER efficiently and specifically labels endocardial cells but not coronary blood vessels in the adult heart. The adult endocardial cells do not contribute to any vascular ECs during cardiac homeostasis. To examine the formation of blood vessels from Endocardium after injury, we generate 4 cardiac injury models with Npr3-CreER mice: myocardial infarction, myocardial ischemia–reperfusion, cryoinjury, and transverse aortic constriction. Lineage tracing experiments show that adult Endocardium minimally contributes to coronary ECs after myocardial infarction. In the myocardial ischemia–reperfusion, cryoinjury, or transverse aortic constriction models, adult endocardial cells do not give rise to any vascular ECs, and they remain on the inner surface of myocardium that connects with lumen circulation. In the myocardial infarction model, very few endocardial cells are trapped in the infarct zone of myocardium shortly after ligation of coronary artery, indicating the involvement of endocardial entrapment during blood vessels formation. When these adult endocardial cells are relocated and trapped in the infarcted myocardium by transplantation or myocardial constriction model, very few endocardial cells survive and gain vascular EC properties, and their contribution to neovascularization in the injured myocardium remains minimal. Conclusions: Unlike its fetal or neonatal counterpart, adult Endocardium naturally generates minimal, if any, coronary arteries or vascular ECs during cardiac homeostasis or after injuries.
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Endocardium minimally contributes to coronary endothelium in the embryonic ventricular free walls
Circulation Research, 2016Co-Authors: Hui Zhang, Wenjuan Pu, Guang Li, Xiuzhen Huang, Lingjuan He, Xueying Tian, Libo Zhang, Sean M Wu, Henry M Sucov, Bin ZhouAbstract:Rationale:There is persistent uncertainty regarding the developmental origins of coronary vessels, with 2 principal sources suggested as ventricular Endocardium or sinus venosus (SV). These 2 proposed origins implicate fundamentally distinct mechanisms of vessel formation. Resolution of this controversy is critical for deciphering the programs that result in the formation of coronary vessels and has implications for research on therapeutic angiogenesis. Objective:To resolve the controversy over the developmental origin of coronary vessels. Methods and Results:We first generated nuclear factor of activated T cells (Nfatc1)-Cre and Nfatc1-Dre lineage tracers for Endocardium labeling. We found that Nfatc1 recombinases also label a significant portion of SV endothelial cells in addition to Endocardium. Therefore, restricted endocardial lineage tracing requires a specific marker that distinguishes Endocardium from SV. By single-cell gene expression analysis, we identified a novel endocardial gene natriuretic p...
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Endocardium contributes to cardiac fat
Circulation Research, 2016Co-Authors: Hui Zhang, Wenjuan Pu, Xiuzhen Huang, Lingjuan He, Xueying Tian, Libo Zhang, Shengshou Hu, Bin ZhouAbstract:Rationale: Unraveling the developmental origin of cardiac fat could offer important implications for the treatment of cardiovascular disease. The recent identification of the mesothelial source of epicardial fat tissues reveals a heterogeneous origin of adipocytes in the adult heart. However, the developmental origin of adipocytes inside the heart, namely intramyocardial adipocytes, remains largely unknown. Objective: To trace the developmental origin of intramyocardial adipocytes. Methods and Results: In this study, we identified that the majority of intramyocardial adipocytes were restricted to myocardial regions in close proximity to the Endocardium. Using a genetic lineage tracing model of endocardial cells, we found that Nfatc1+ endocardial cells contributed to a substantial number of intramyocardial adipocytes. Despite the capability of the Endocardium to generate coronary vascular endothelial cells surrounding the intramyocardial adipocytes, results from our lineage tracing analyses showed that intramyocardial adipocytes were not derived from coronary vessels. Nevertheless, the Endocardium of the postnatal heart did not contribute to intramyocardial adipocytes during homeostasis or after myocardial infarction. Conclusions: Our in vivo fate-mapping studies demonstrated that the developing Endocardium, but not the vascular endothelial cells, gives rise to intramyocardial adipocytes in the adult heart. # Novelty and Significance {#article-title-47}
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hand2 is an essential regulator for two notch dependent functions within the embryonic Endocardium
Cell Reports, 2014Co-Authors: Nathan J Vandusen, Bin Zhou, Jose Casanovas, Joshua W Vincentz, Beth A Firulli, Marco Osterwalder, Javier Lopezrios, Rolf Zeller, Joaquim Gregobessa, Jose Luis De La PompaAbstract:Summary The basic-helix-loop-helix (bHLH) transcription factor Hand2 plays critical roles during cardiac morphogenesis via expression and function within myocardial, neural crest, and epicardial cell populations. Here, we show that Hand2 plays two essential Notch-dependent roles within the Endocardium. Endocardial ablation of Hand2 results in failure to develop a patent tricuspid valve, intraventricular septum defects, and hypotrabeculated ventricles, which collectively resemble the human congenital defect tricuspid atresia. We show endocardial Hand2 to be an integral downstream component of a Notch Endocardium-to-myocardium signaling pathway and a direct transcriptional regulator of Neuregulin1 . Additionally, Hand2 participates in Endocardium-to-Endocardium-based cell signaling, with Hand2 mutant hearts displaying an increased density of coronary lumens. Molecular analyses further reveal dysregulation of several crucial components of Vegf signaling, including VegfA , VegfR2 , Nrp1 , and VegfR3 . Thus, Hand2 functions as a crucial downstream transcriptional effector of endocardial Notch signaling during both cardiogenesis and coronary vasculogenesis.
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down syndrome critical region 1 is a transcriptional target of nuclear factor of activated t cells c1 within the Endocardium during heart development
Journal of Biological Chemistry, 2007Co-Authors: Hai Wu, Bin Zhou, Tomasa Barrientos, Scott Baldwin, Eric N Olson, Gerald R Crabtree, Ching Pin ChangAbstract:Abstract Patients with Down syndrome have characteristic heart valve lesions resulting from endocardial cushion defects. The Down syndrome critical region 1 (DSCR1) gene, identified at the conserved trisomic 21 region in those patients, encodes a calcineurin inhibitor that inactivates nuclear factor of activated T cells (NFATc) activity. Here, we identify a regulatory sequence in the promoter region of human DSCR1 that dictates specific expression of a reporter gene in the Endocardium, defined by the temporal and spatial expression of Nfatc1 during heart valve development. Activation of this evolutionally conserved DSCR1 regulatory sequence requires calcineurin and NFATc1 signaling in the Endocardium. NFATc1 proteins bind to the regulatory sequence and trigger its enhancer activity. NFATc1 is sufficient to induce the expression of Dscr1 in cells that normally have undetectable or minimal NFATc1 or DSCR1. Pharmacologic inhibition of calcineurin or genetic Nfatc1 null mutation in mice abolishes the endocardial activity of this DSCR1 enhancer. Furthermore, in mice lacking endocardial NFATc1, the endogenous Dscr1 expression is specifically inhibited in the Endocardium but not in the myocardium. Thus, our studies indicate that the DSCR1 gene is a direct transcriptional target of NFATc1 proteins within the Endocardium during a critical window of heart valve formation.
Rie Saba - One of the best experts on this subject based on the ideXlab platform.
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Endocardium differentiation through sox17 expression in Endocardium precursor cells regulates heart development in mice
Scientific Reports, 2019Co-Authors: Rie Saba, Keiko Kitajima, Lucille Rainbow, Sylvia Engert, Mami Uemura, Hidekazu Ishida, Ioannis KokkinopoulosAbstract:The Endocardium is the endothelial component of the vertebrate heart and plays a key role in heart development. Where, when, and how the Endocardium segregates during embryogenesis have remained largely unknown, however. We now show that Nkx2-5+ cardiac progenitor cells (CPCs) that express the Sry-type HMG box gene Sox17 from embryonic day (E) 7.5 to E8.5 specifically differentiate into the Endocardium in mouse embryos. Although Sox17 is not essential or sufficient for Endocardium fate, it can bias the fate of CPCs toward the Endocardium. On the other hand, Sox17 expression in the Endocardium is required for heart development. Deletion of Sox17 specifically in the mesoderm markedly impaired Endocardium development with regard to cell proliferation and behavior. The proliferation of cardiomyocytes, ventricular trabeculation, and myocardium thickening were also impaired in a non-cell-autonomous manner in the Sox17 mutant, likely as a consequence of down-regulation of NOTCH signaling. An unknown signal, regulated by Sox17 and required for nurturing of the myocardium, is responsible for the reduction in NOTCH-related genes in the mutant embryos. Our results thus provide insight into differentiation of the Endocardium and its role in heart development.
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sox17 expression in Endocardium precursor cells regulates heart development in mice
bioRxiv, 2019Co-Authors: Rie Saba, Keiko Kitajima, Lucille Rainbow, Sylvia Engert, Mami Uemura, Hidekazu Ishida, Ioannis Kokkinopoulos, Yasunori Shintani, Shigeru MiyagawaAbstract:The Endocardium is the endothelial component of the vertebrate heart and plays a key role in heart development. Cardiac progenitor cells (CPCs) that express the homeobox gene Nkx2-5 give rise to the Endocardium. Where, when, and how the Endocardium segregates during embryogenesis have remained largely unknown, however. We now show that Nkx2-5+ CPCs that express the Sry-type HMG box gene Sox17 specifically differentiate into the Endocardium in mouse embryos. Approximately 20% to 30% of Nkx2-5+ CPCs transiently express Sox17 from embryonic day (E) 7.5 to E8.5. Although Sox17 is not essential or sufficient for Endocardium fate, it can bias the fate of CPCs toward the Endocardium. On the other hand, Sox17 expression in the Endocardium is required for heart development. Deletion of Sox17 specifically in the mesoderm markedly impaired Endocardium development with regard to cell proliferation and behavior. The proliferation of cardiomyocytes, ventricular trabeculation, and myocardium thickening were also impaired in a non-cell-autonomous manner in the Sox17 mutant, resulting in anomalous morphology of the heart, likely as a consequence of down-regulation of NOTCH signaling. Changes in gene expression profile in both the Endocardium and myocardium preceded the reduction in NOTCH-related gene expression in the mutant embryos, suggesting that Sox17 expression in the Endocardium regulates an unknown signal required for nurturing of the myocardium. Our results thus provide insight into differentiation of the Endocardium and its role in heart development.
Jose Luis De La Pompa - One of the best experts on this subject based on the ideXlab platform.
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bmp2 and notch cooperate to pattern the embryonic Endocardium
Development, 2018Co-Authors: Jose Luis De La Pompa, Tania Papoutsi, Luis Lunazurita, Belen Prados, Stephane ZaffranAbstract:Signaling interactions between myocardium and Endocardium pattern embryonic cardiac regions, instructing their development to fulfill specific functions in the mature heart. We show that ectopic Bmp2 expression in the mouse chamber myocardium changes the transcriptional signature of adjacent chamber endocardial cells into valve tissue, and enables them to undergo epithelial-mesenchyme transition. This induction is independent of valve myocardium specification and requires high levels of Notch1 activity. Biochemical experiments suggest that Bmp2-mediated Notch1 induction is achieved through transcriptional activation of the Notch ligand Jag1, and physical interaction of Smad1/5 with the intracellular domain of the Notch1 receptor. Thus, widespread myocardial Bmp2 and endocardial Notch signaling drive presumptive ventricular Endocardium to differentiate into valve Endocardium. Understanding the molecular basis of valve development is instrumental to designing therapeutic strategies for congenital heart valve defects.
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notch signalling restricts inflammation and serpine1 expression in the dynamic Endocardium of the regenerating zebrafish heart
Development, 2017Co-Authors: Jose Luis De La Pompa, Juliane Munch, Dimitrios Grivas, Alvaro Gonzalezrajal, Rebeca TorregrosacarrionAbstract:The zebrafish heart regenerates after ventricular damage through a process involving inflammation, fibrotic tissue deposition/removal and myocardial regeneration. Using 3D whole-mount imaging, we reveal a highly dynamic Endocardium during cardiac regeneration, including changes in cell morphology, behaviour and gene expression. These events lay the foundation for an initial expansion of the Endocardium that matures to form a coherent endocardial structure within the injury site. We studied two important endocardial molecules, Serpine1 and Notch, which are implicated in different aspects of endocardial regeneration. Notch signalling regulates developmental gene expression and features of endocardial maturation. Also, Notch manipulation interferes with attenuation of the inflammatory response and cardiomyocyte proliferation and dedifferentiation. serpine1 is strongly expressed very early in the wound Endocardium, with decreasing expression at later time points. serpine1 expression persists in Notch-abrogated hearts, via what appears to be a conserved mechanism. Functional inhibition studies show that Serpine1 controls endocardial maturation and proliferation and cardiomyocyte proliferation. Thus, we describe a highly dynamic Endocardium in the regenerating zebrafish heart, with two key endocardial players, Serpine1 and Notch signalling, regulating crucial regenerative processes.
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hand2 is an essential regulator for two notch dependent functions within the embryonic Endocardium
Cell Reports, 2014Co-Authors: Nathan J Vandusen, Bin Zhou, Jose Casanovas, Joshua W Vincentz, Beth A Firulli, Marco Osterwalder, Javier Lopezrios, Rolf Zeller, Joaquim Gregobessa, Jose Luis De La PompaAbstract:Summary The basic-helix-loop-helix (bHLH) transcription factor Hand2 plays critical roles during cardiac morphogenesis via expression and function within myocardial, neural crest, and epicardial cell populations. Here, we show that Hand2 plays two essential Notch-dependent roles within the Endocardium. Endocardial ablation of Hand2 results in failure to develop a patent tricuspid valve, intraventricular septum defects, and hypotrabeculated ventricles, which collectively resemble the human congenital defect tricuspid atresia. We show endocardial Hand2 to be an integral downstream component of a Notch Endocardium-to-myocardium signaling pathway and a direct transcriptional regulator of Neuregulin1 . Additionally, Hand2 participates in Endocardium-to-Endocardium-based cell signaling, with Hand2 mutant hearts displaying an increased density of coronary lumens. Molecular analyses further reveal dysregulation of several crucial components of Vegf signaling, including VegfA , VegfR2 , Nrp1 , and VegfR3 . Thus, Hand2 functions as a crucial downstream transcriptional effector of endocardial Notch signaling during both cardiogenesis and coronary vasculogenesis.