The accumulation of vascular smooth muscle cells in the arterial intima is a major component of atherosclerosis and is a significant limiting factor in angioplasty, vascular bypass surgery and organ transplantation. Vascular smooth muscle cell proliferation is controlled in part by the combined action of heparin-binding growth factors and the glycosaminoglycans heparin/heparin sulfate. One growth factor in particular, basic fibroblast growth factor (bFGF) appears to play an important role. bFGF binds to heparin sulfate proteoglycans (HSPGs) and this interaction has been shown to both facilitate and inhibit binding of bFGF to its receptors on the cell surface, as well as provide a means for fFGF storage within the extracellular matrix. The overall goals of this proposal are i) to gain a quantitative understanding of how HSPGs control the interaction and activity of fFGF in vascular smooth muscle cells (SMC), and ii) to determine the characteristics of HSPGs that dictate their function. Our preliminary studies indicate that i) HSPGs mediate high affinity binding of bFGF by prolonging the period of receptor occupancy and not by facilitating bFGF-receptor association, ii) HSPG in the extracellular matrix store heparin-binding growth factors by continued dynamic binding and re-binding which can effectively compete for and control cell surface binding, and iii) that the biological response of vascular smooth muscle cells to bFGF in vivo and in vitro is inhibited by HSPGs secreted by endothelial cells.
The specific Aims of this proposal are: 1. To analyze bFGF binding, internalization and processing in vascular smooth muscle cells, and determine how these events are controlled by heparin sulfate proteoglycans, 2. To characterize how heparin sulfate proteoglycans modulate the activity of bFGF on vascular smooth muscle cells, and 3. To determine the characteristics that govern heparin sulfate proteoglycan function. They will analyze the kinetics of the multi-step bFGF-cell interaction pathway in native and HSPG deficient smooth muscle cells, and will correlate these data with biochemical and biological activity measurements to determine the critical steps for activity. They will isolate a series of HSPGs from vascular smooth muscle and endothelial cells. They will systematically characterize the physical structure and activity (ability to bind bFGF, bind SMC and modulate bFGF cell binding and mitogenesis) of each HSPG. Ultimately they plan to develop a mechanistic model that will allow the relative roles of specific HSPG characteristics to be elucidated. These models would be valuable in the design of specific synthetic growth factor inhibitors and activators that might have applications in a number of clinical situations.
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