The aim of this proposal is to define the molecular mechanism involved in the control of endothelial cell growth, with specific emphasis on the role of growth-inhibitory extracellular matrix (ECM) heparan sulfate proteoglycans. Acidic fibroblast growth factor (aFGF) modulates synthesis of ECM components which can modulate the cell's proliferative response to aFGF. Heparan sulfate proteoglycans (HSPG) have been isolated from ECM which inhibit aFGF-stimulated proliferation of endothelial cells. The internalization of this inhibitory HSPG is enhanced by aFGF. The aims of this proposal are to characterize the structures, interactions, and functions of inhibitory HSPG. The regulation of incorporation of inhibitory HSPG into ECM by aFGF will be investigated. The long term objective is to elucidate the molecular mechanism of regulation of endothelial cell growth control. The idea to be explored in this study is that cellular proliferation or quiescence is regulated by complex interactions involving various cellular products, including microenvironmental ECM components and soluble growth factors, all of which are manufactured either by the cell itself or its neighbors. The results will be of great interest to all scientists studying cellular growth control or the interaction of cells with their ECM environment.
