The overall goal of this project is to elucidate the temporal-spatial and synergistic roles of growth factors in the regulation of events comprising coronary vascularization during heart development. The investigators will conduct (1) in vivo experiments to document the overall temporal-spatial effects of specific growth factors and receptors, and (2) in vitro experiments to determine the effects of growth factors on specific events necessary for vascularization. Both avian (quail) and mammalian (rat) models will be used for protocols which include localizing growth factor protein and mRNA expression, assaying for cell proliferation and migration, and blocking specific growth factors and their receptors.
The first aim i s to establish the role of these growth factors in the early phase of myocardial vascularization which is dominated by vasculogenesis. Hypotheses to be tested address the roles of the tie-2 receptor and its ligand, angiopoietin-1, and VEGF and bFGF and their receptors.
Aim 2 is to determine the growth factors which regulate the subsequent phase of vascularization dominated by sprouting (angiogenesis). The hypotheses focus on (1) VEGF and bFGF as regulators of angiogenesis, (2) local growth factor signaling as a mechanism for guiding endothelial cell cords into the aorta to form the coronary arteries, and (3) the roles of PDGF and bFGF as the primary regulators of smooth muscle migration and assembly into the media of the coronary arteries.
Aim 3 will test two hypotheses: (1) hypoxia serves as a metabolic stimulus for the upregulation of VEGF mRNA in embryonic and neonatal cardiomyocytes; (2) stretch of endothelial cells increases their responsiveness to growth factors, and stretch of cardiomyocytes upregulates VEGF and bFGF expression. These studies will demonstrate, for the first time, the temporal-spatial regulation of coronary vessel formation by key growth factors critical to the vascularization cascade. Understanding coronary vasculogenesis and angiogenesis will provide an important foundation for understanding cardiac defects, since myocardial growth is dependent upon timely and adequate vascularization.
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