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Endothelial Differentiation and Morphogenesis of Cardiac Precursors

Posted in Cardiovascular Pharmacogenomics, tagged congenital heart defects, development, embryo, embryogenesis, Endothelium, gene expression, heart development, transcription factors, vasculogenesis on July 17, 2012| 3 Comments »

Reporter: Sudipta Saha, Ph.D.

Beyond characterization of the fundamental anatomy of vascular development, the first investigators in this field participated in one of the classic debates in all of developmental biology: where and when do endothelial cells (and hence blood vessels) arise in the developing embryo? Because blood vessels are first observed in the yolk sac in avian and mammalian embryos. It was initially assumed that all blood vessels arise from extra-embryonic tissues. However, careful histological analysis subsequently indicated that isolated foci of endothelial cells can also be observed in the embryo proper, which suggested that blood vessels arise from an intraembryonic source (specifically, the mesoderm) rather than via colonization. The formation of new blood vessels in the adult organism not only contributed to the progression of diseases such as cancer and diabetic retinopathy but also can be promoted in therapeutic approaches to various ischemic pathologies. Because many of the signals important to blood vessel development during embryogenesis are recapitulated during adult blood vessel formation, much work has been performed to better-understand the molecular control of endothelial differentiation in the developing embryo. Activators and inhibitors of developmental pathways have been tested for their ability to modulate angiogenesis in early phase clinical trials, and in the case of anti-Flk1 antibodies clinical utility has been demonstrated for anti-tumor strategies. Analyses of circulating endothelial progenitor cells, which have angiogenic potential, do indeed suggest that there are similarities in the biology of these cells compared with developmental endothelial precursors. Stem cell therapeutics therefore represents another potential arena for translation of insights from vascular development to clinical practice. Even though our understanding of endothelial development is much richer than it was even a few years ago and despite the potential applications of this knowledge in clinical medicine, there are still a number of key issues on this topic that remain to be resolved. Precisely how early are endothelial precursors specified during development, and what is the nature of this progenitor cell pool? What are the relationships among signaling pathways that specify endothelial fates in a coordinated fashion? Is there a transcriptional hierarchy that regulates vascular development? The answers to these and other questions about endothelial development are likely to be forthcoming in the near future as experimental methods continue to evolve (http://atvb.ahajournals.org/content/25/11/2246.full).

The development of the vertebrate heart can be considered an additive process, in which additional layers of complexity have been added throughout the evolution of a simple structure (linear heart tube) in the form of modular elements (atria, ventricles, septa, and valves). Each modular element confers an added capacity to the vertebrate heart and can be identified as individual structures patterned in a precise manner. An understanding of the individual modular steps in cardiac morphogenesis is particularly relevant to congenital heart disease, which usually involves defects in specific structural components of the developing heart. Organ formation requires the precise integration of cell type-specific gene expression and morphological development; both are intertwined in their regulation by transcription factors. Although many transcription factors have been described as regulators of cardiac-specific gene expression, the transcriptional regulation of cardiac morphogenesis is still not well explored. For a transcription factor to be considered directly involved in heart development, it must be expressed in developing heart tissues and exert an influence on processes that impact the morphogenesis of the developing heart. Transcription factors can regulate the expression of other genes in a tissue-specific and quantitative manner and are thus major regulators of embryonic developmental processes. A number of complex transcriptional networks and interactions are involved in the morphogenesis of the developing vertebrate heart. The identities of crucial regulators involved in defined events in cardiogenesis are being uncovered at a rapid rate, but a number of critical questions remain. First and foremost, it is still not known which transcription factors are involved in the earliest differentiation of cardiac cells from the mesoderm. Second, the downstream pathways regulated by transcription factors responsible for key morphogenetic events are still largely unknown. Third, the concept of maintained function or redeployment of functions throughout various stages of development remains to be addressed in detail. The challenge for the future lies in defining pathways downstream from cardiac transcription factors and understanding the intersection of these pathways as the heart develops from a simple patterned structure into a complex multifunctional organ (http://circres.ahajournals.org/content/90/5/509.full).

Tissue development and regeneration involve tightly coordinated and integrated processes: selective proliferation of resident stem and precursor cells, differentiation into target somatic cell type, and spatial morphological organization. The role of the mechanical environment in the coordination of these processes is poorly understood. It has been reported that multipotent cells derived from native cardiac tissue continually monitored cell substratum rigidity and showed enhanced proliferation, endothelial differentiation, and morphogenesis when the cell substratum rigidity closely matched that of myocardium. Mechanoregulation of these diverse processes required p190RhoGAP, a guanosine triphosphatase-activating protein for RhoA, acting through RhoA-dependent and -independent mechanisms. Natural or induced decreases in the abundance of p190RhoGAP triggered a series of developmental events by coupling cell-cell and cell-substratum interactions to genetic circuits controlling differentiation (http://www.ncbi.nlm.nih.gov/pubmed/22669846).