Congestive heart failure is a public health problem that affects 4.9 million Americans (lifetime risk approximately 20%). Fibroblast Growth Factors (FGFs) have been proposed as important molecules for development and function of the cardiovascular system and as important angiogenic factors. In this proposal, mouse models will be used to investigate the role of FGF signaling in cardiac development, coronary vasculogenesis and cardiac hypertrophy. Despite a wealth of in vitro data showing that cardiomyoblasts and endothelial cells respond to FGFs, there is a paucity of data that actually links FGF signaling to cardiovascular development and physiology in vivo. We have demonstrated that Fgf9 null embryos die at birth with arrested pulmonary development, a congestive cardiomyopathy and a delay in coronary vasculogenesis. We also show that mice lacking both FGFR1 and FGFR2 (double conditional knockout) in the myocardium display a profound arrest in heart development and coronary vasculogenesis. The proposed experiments will allow us to test the hypothesis that FGF signaling promotes the expansion of the cardiomyoblast population and development of the coronary vasculature during midgestation heart development. We will examine changes in expression levels and patterns of genes known to functionally interact with FGFs in mice lacking myocardial Fgfrs 1 and 2. We will rigorously test and refine our working model that FGF signaling mediates coronary vasculogenesis through a Hedgehog (HH)/VEGF-A dependent pathway and cardiomyoblast expansion through a HH independent pathway. Furthermore, we propose that BMP signals antagonize coronary vasculogenesis and myocardial expansion separately through inhibition of HH and FGF pathways, respectively. In adult mice, we will test the hypothesis that FGFR signaling is required to maintain myocardial homeostasis and to mediate the hypertrophic response to pressure overload.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CDD (01))
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Schramm, Charlene A
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Washington University
Other Basic Sciences
Schools of Medicine
Saint Louis
United States
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