This proposal will employ quail (Aim 1) and mice (Aim 2-4) to address the overall hypothesis that the continuum of events required to form the hierarchy of the coronary vascular tree requires a complex interplay of cells and molecular signals which are temporally regulated. Experiments in Aim 1 will use in vitro (heart explants) and in ovo approaches to establish the specificity, interactions, and signaling of growth factors that regulate coronary vasculogenesis and angiogenesis during the stages preceding coronary artery formation.
Aim 2 will determine the harmonic interplay of growth factors that facilitate postnatal coronary artery growth by examining the assembly, growth and remodeling of the coronary arterial tree. Neutralizing antibodies to growth factors and soluble receptors will be used in Aims 1 and 2 in order to test hypotheses regarding the specific roles of growth factors in various components of the vasculogenic/angiogenic cascade.
Aim 3 will address the contribution of bone marrow-derived cells to coronary vessel formation during development. This novel aim tests the hypothesis that these cells are activated by specific growth factors and constitute a second source of precursor cells (the first being the epicardial, subepicardial region) that contribute to early postnatal formation of the coronary vasculature. Finally, Aim 4 addresses cyclic and static stretch, as key players in activating angiogenic growth factors and receptors of both cardiomyocytes and endothelial cells. Three unique features of these studies are that they 1) address the continuum of events constituting the development of the coronary tree and the growth factors which regulate these events, 2) are the first to address bone marrow-derived cells as contributors to the coronary vessels during development, and 3) explore stretch as a growth associated stimulus for myocardial vascularization. Since cardiac development depends on timely and adequate vascularization, an understanding of coronary vasculogenesis and angiogenesis will provide an important foundation for our understanding of cardiac defects.
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