Cardiovascular disease is the number one cause of death in the United States. The migration and growth of vascular smooth muscle cells within the arterial intima is a hallmark of atherosclerosis and is a major limiting factor in angioplasty, vascular bypass surgery and organ transplantation. Although heparin and heparan sulfate proteoglycans (HSPG) have been identified as potent inhibitors of vascular smooth muscle cell growth, these same molecules have also been shown to enhance the proliferative activity of heparin-binding growth factors such as basic fibroblast growth factor (FGF2). The mechanisms of vascular cell growth regulation by HSPG are complex and remain poorly defined. The dual function of HSPG as growth factor stimulators and inhibitors appears to relate to the specific HSPG structure and localization within cells and the extracellular matrix. Consequently, the overall goals of this proposal are 1) to determine how HSPGs control the activity of heparin-binding growth factors in vascular smooth muscle cells, and 2) to identify the factors that dictate the function of endothelial-derived HSPG, perlecan. We will conduct parallel studies on, 1) the regulation of intracellular trafficking and activity of FGF2 and heparin-binding EGF-like growth factor (HB-EGF) by HSPG in smooth muscle cells (SMC), and 2) the physical and chemical characteristics of endothelial cell perlecan that dictate its ability to regulate heparin-binding growth factor activity.
The specific aims of this proposal are to identify mechanisms of intracellular processing of FGF2 and HB-EGF in SMC, define the relationship between HSPG and FGF2 activity in SMC, and establish the structure/function relationships for endothelial derived-perlecan. Our studies will provide critical information on the intracellular function of growth factors and HSPG and will potentially identify conditions where the homeostatic balance between vascular repair and disease can be manipulated by targeting the HSPGs involved. These studies will provide important insight into the rational design of new therapies aimed at intervening in the vascular disease process to facilitate repair.
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