Angiogenesis represents an important element of tissue response to ischemia or wounding, and tumorstimulated neovascularization plays a critical role in cancer's growth and expansion. At the same time, relatively little new vessel growth takes place in most adult tissues including the myocardium. Although regulation of angiogenic response is an important part of normal and pathological homeostasis, little is known about the mechanisms of this control. Previous work from our laboratory, as well as from others, has established the important role of syndecan-4 protein in mediation of FGF2 signaling in endothelial cells. In particular, we have been able to show that syndecan-4 expression enhances cellular responses to FGF2 while introduction of syndecan-4 dominant-negative constructs selectively blocks FGF2 (but not PDGF or EGF) signaling. However, events involved in syndecan-4-mediated signaling are poorly understood. In this grant application, we propose to explore these issues in the context of angiogenesis. In particular, we will study the effect of syndecan-4 translocation from the lateral to the apical membrane surface on FGF2- induced cell growth and migration and define its molecular mechanisms. It is hoped that better understanding of syndecan-4-dependent regulation of FGF2 signaling in endothelial cell function will provide new insights into the regulation of angiogenesis. ? ?
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