Coronary artery disease accounts for 54% of all cardiovascular disease in the United States [1]. Understanding how coronary vessels develop is likely to uncover novel drug targets and therapeutic strategies useful in directing the repair or remodeling of coronary vessels in adults. Recent data from our laboratory has demonstrated that targeted deletion of the Type III Transforming Growth Factor 2 receptor (TGF2R3) results in embryonic death associated with failure of the formation or persistence of the coronary vessels while other vascular beds appear to develop normally. Experiments are proposed to identify how the loss of TGF2R3 results in the failure of coronary vessel development and to reveal the TGF2 signaling pathways that regulate epicardial cell differentiation. We will test 3 specific hypotheses. Hypothesis 1: TGF2R3 is required for proper epicardial differentiation. This will be tested by in vivo analysis of the epicardium and epicardial derivatives in wildtype, heterozygous Tgfbr3 null, and homozygous Tgfbr3 null animals. Hypothesis 2: TGF2R3 is required in the epicardium or myocardium for proper coronary vessel development. This will be tested by conditional deletion of Tgfbr3 in the epicardium and myocardium. Hypothesis 3: Specific TGF2 signaling pathways regulate epicardial cell differentiation. This will be tested in vitro in both explants and immortalized cells from wildtype, heterozygous Tgfbr3 null, and homozygous Tgfbr3 null animals The successful completion of the proposed experiments will yield significant insight into the role of Transforming Growth Factor 2 (TGF2) in coronary vessel development. The unique nature of the derivation of the coronary vessels and the significance of coronary vessel disease in humans makes the determination of the mechanisms behind TGF2R3 regulation of coronary vasculogenesis of high significance from both a basic science and clinical perspective.
