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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076664-04
Application #
7323277
Study Section
Special Emphasis Panel (ZRG1-CDD (01))
Program Officer
Schramm, Charlene A
Project Start
2004-12-15
Project End
2009-11-30
Budget Start
2007-12-01
Budget End
2009-11-30
Support Year
4
Fiscal Year
2008
Total Cost
$362,679
Indirect Cost
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Lavine, Kory J; Kovacs, Attila; Ornitz, David M (2008) Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice. J Clin Invest 118:2404-14
Lavine, Kory J; Ornitz, David M (2008) Fibroblast growth factors and Hedgehogs: at the heart of the epicardial signaling center. Trends Genet 24:33-40
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Lavine, Kory J; Ornitz, David M (2007) Rebuilding the coronary vasculature: hedgehog as a new candidate for pharmacologic revascularization. Trends Cardiovasc Med 17:77-83
Lin, Yongshun; Liu, Guoqin; Zhang, Yongyou et al. (2007) Fibroblast growth factor receptor 2 tyrosine kinase is required for prostatic morphogenesis and the acquisition of strict androgen dependency for adult tissue homeostasis. Development 134:723-34
Zhang, Xiuqin; Ibrahimi, Omar A; Olsen, Shaun K et al. (2006) Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 281:15694-700
Lavine, Kory J; White, Andrew C; Park, Changwon et al. (2006) Fibroblast growth factor signals regulate a wave of Hedgehog activation that is essential for coronary vascular development. Genes Dev 20:1651-66

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