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Cardiovascular Projects:
Fibroblast Growth Factors (FGFs) have been proposed as important regulators of growth and function of the heart and as important angiogenic factors. The observation that cardiomyoblasts and endothelial cells are responsive to FGF signals has been known since the discovery of FGFs in the early 1970s, yet very little is known about the in vivo function of FGFs during the critical midgestation stage of myocardial growth and coronary vascular system development. Furthermore, no information is available on the role of FGF signaling in the neonatal heart. Fgf2 has been the focus of many studies and Fgf2 is expressed during myocardial development and is strongly induced following myocardial injury. However, there has been little direc
t evidence for a function of FGF2 in myocardial development, but increasing evidence for a role for FGF2 in the response to injury. This could reflect redundancy among multiple FGF ligands expressed during heart development. We have demonstrated that mice lacking both FGF receptor 1 (FGFR1) and FGFR2 (double conditional knockout, DCKO) in the cardiomyoblast have defects in myocardial growth during midgestation heart development. The defects seen with receptor loss could be partially reproduced when Fgf9 (expressed in the epicardium and endocardium) was deleted, indicating likely redundancy of FGF9 with other FGFs. Furthermore, given that cardiomyoblasts still grow, even in the absence of FGFR1/FGFR2, we hypothesize that other signaling pathways must work together with FGF pathways to regulate myocardial growth. These experiments prove that FGFR signaling does indeed function in cardiomyoblast growth and suggests a potentially more significant role for FGF signaling in myocardial pathology and response to injury. Importantly, we have also shown that FGFR signaling within the cardiomyoblast is required for coronary vascular development. However, we found this sign al to be indirect and complex, involving signaling interactions between the myocardium, epicardium and perivascular mesenchyme. We have begun to define the underlying mechanism by identifying a signaling pathway in which FGF signaling within the cardiomyoblast activates sonic hedgehog (Shh) expression in the epicardium. Two cell types, the cardiomyoblast and perivascular fibroblast, respond to SHH by activating expression of vasculogenic factors (Vegf and Angiopoietin 2). However, the mechanism by which the cardiomyoblast regulates epicardial function and expression of Shh is still not known. Our studies have defined the epicardium as an essential signaling center that functions to provide FGF and hedgehog (HH) signals to regulate and coordinate myocardial growth and coronary vascular development. Ongoing projects will identify signals that originate within the myocardium that regulate epicardial function. In neonatal mice, we are examining whether FGF signaling can enhance myocardial growth and hypertrophy and result in improved cardiac function in the adult.
Related publications:
Lavine, K.J., Yu, K., White, A.C., Zhang, X., Smith, C., Partanen, J., and Ornitz, D.M. (2005). Endocardial and epicardial derived FGF signals regulate myocardial proliferation and differentiation in vivo. Dev Cell 8, 85-95.
Lavine, K.J., White, A.C., Park, C., Smith, C.S., Choi, K., Long, F., Hui, C.C., and Ornitz, D.M. (2006). Fibroblast growth factor signals regulate a wave of Hedgehog activation that is essential for coronary vascular development. Genes Dev 20, 1651-1666.
Lavine, K.J., and Ornitz, D.M. (2007). Rebuilding the coronary vasculature: hedgehog as a new candidate for pharmacological revascularization. Trends Cardiovasc Med 17, 77-83.
Lavine, K.J., and Ornitz, D.M. (2008). Fibroblast Growth Factors and Hedgehogs: At the Heart of the Epicardial Signaling Center. Trends Genet 24, 33-40.