RESUMO
It has been established that coronary vessels develop through self-assembly of mesenchymal vascular progenitors in the subepicardium. Mesenchymal precursors of vascular smooth muscle cells and fibroblasts are known to originate from an epithelial-to-mesenchymal transformation of the epicardial mesothelium, but the origin of the coronary endothelium is still obscure. We herein report that at least part of the population of the precursors of the coronary endothelium are epicardially-derived cells (EPDCs). We have performed an EPDC lineage study through retroviral and fluorescent labelling of the proepicardial and epicardial mesothelium of avian embryos. In all the experiments onlythe surface mesothelium was labelled after 3 h of reincubation. However, endothelial cells from subepicardial vessels were labelled after 24-48 h and endothelial cells of intramyocardial vessels were also labelled after 48-96 h of reincubation. In addition, the development of the coronary vessels was studied in quail-chick chimeras, obtaining results which also support a mesothelial origin for endothelial and smooth muscle cells. Finally, quail proepicardial explants cultured on Matrigel showed colocalization of cytokeratin and QH1 (mesothelial and endothelial markers, respectively) after 24 h. These results, taken together, suggest that EPDC show similar competence to that displayed by bipotential vascular progenitor cells [Yamashita et al., Nature 408: 92-96 (2000)] which are able to differentiate into endothelium or smooth muscle depending on their exposure to VEGF or PDGF-BB. It is conceivable that the earliest EPDC differentiate into endothelial cells in response to myocardially-secreted VEGF, while further EPDC would be recruited by the nascent capillaries via PDGFR-beta signalling, giving rise to mural cells.
Assuntos
Endotélio Vascular/citologia , Miocárdio/patologia , Animais , Becaplermina , Diferenciação Celular , Embrião de Galinha , Colágeno/farmacologia , Combinação de Medicamentos , Fatores de Crescimento Endotelial/metabolismo , Endotélio Vascular/patologia , Fibroblastos/metabolismo , Coração/embriologia , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Laminina/farmacologia , Linfocinas/metabolismo , Microscopia de Fluorescência , Modelos Biológicos , Miocárdio/citologia , Miocárdio/metabolismo , Técnicas de Cultura de Órgãos , Pericárdio/citologia , Pericárdio/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteoglicanas/farmacologia , Proteínas Proto-Oncogênicas c-sis , Codorniz , Retroviridae/genética , Retroviridae/metabolismo , Transdução de Sinais , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Coronary vessels develop from a primary vascular network that differentiates in the subepicardium through a process of vasculogenesis, that is, self-assembly of mesenchymal vascular progenitors. Further growth of the subepicardial vascular plexus through a complex process of angiogenesis, vascular remodeling, and arterialization of specific branches gives rise to the definitive coronary system. This report is intended to summarize current knowledge on the origin of the coronary vascular progenitors and to provide new insights suggested by recent findings. It has been established that the mesenchymal precursors of the vascular smooth muscle cells and the adventitial fibroblasts originate from an epithelial-mesenchymal transformation of the epicardial mesothelium. We report herein experimental evidence that the precursors of the coronary endothelium are also epicardium-derived cells (EPDCs). The evidence shown includes co-localization of mesothelial and endothelial molecular markers as well as cell lineage studies performed through direct labeling of the epicardial cells. If this proposal is confirmed, the early EPDCs might be found to have a competence similar to that shown by the recently discovered bipotential vascular progenitor cells, which are able to differentiate into endothelium or smooth muscle depending on their exposure to VEGF or PDGF-BB. It is conceivable that the earliest EPDCs differentiate into endothelial cells in response to myocardially secreted VEGF, while subsequent EPDCs, recruited by the nascent capillaries via PDGFRbeta signaling, differentiate into percytes and smooth muscle cells.
Assuntos
Anomalias dos Vasos Coronários/embriologia , Anomalias dos Vasos Coronários/fisiopatologia , Endotélio Vascular/embriologia , Endotélio Vascular/fisiopatologia , Endotélio Vascular/crescimento & desenvolvimento , Humanos , Miócitos de Músculo Liso/fisiologiaRESUMO
The epicardium develops from an extracardiac primordium, the proepicardium, which is constituted by a cluster of mesothelial cells located on the cephalic and ventral surface of the liver-sinus venosus limit (avian embryos) or on the pericardial side of the septum transversum (mammalian embryos). The proepicardium contacts the myocardial surface and gives rise to a mesothelium, which grows and progressively lines the myocardium. The epicardium generates, through a process of epithelial-mesenchymal transition, a population of epicardial-derived cells (EPDC). EPDC contribute to the development of cardiac connective tissue, fibroblasts, and the smooth muscle of cardiac vessels. Recent data suggest that EPDC can also differentiate into endothelial cells of the primary subepicardial vascular plexus. If this is confirmed, EPDC would show the same developmental properties that characterize the stem-cell-derived bipotential vascular progenitors recently described, whose differentiation into endothelium and smooth muscle is regulated by exposure to VEGF and PDGF-BB, respectively. Aside from their function in the development of cardiac connective and vascular tissue, EPDC also play an essential modulating role in the differentiation of the compact ventricular layer of the myocardium, a role which might be regulated by the transcription factor WT1 and the production of retinoic acid.