Smooth muscle cells (SMCs), the most abundant cell type in the blood vessel wall, are primarily responsible for contraction and maintenance of vascular tone. They generally have a low replication rate in vivo; however, SMC proliferation is regarded as a key event in the pathogenesis of both atherosclerosis and transplantation-associated arteriosclerosis. SMC proliferation also contributes to the development of restenosis after coronary angioplasty and to the occlusion of synthetic bypass grafts. For these reasons, the long-term goal of our laboratory is to identify the molecular mechanisms that regulate SMC growth in vivo. Acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) are the best characterized members of the FGF family of seven structurally related polypeptides. They are potent SMC mitogens and are expressed by the normal resident cells of the vessel wall. Thus, the first two specific aims of this proposal are: 1) to determine the biological consequences of elevated AFGF or BFGF expression by characterizing SMC lines that produce high levels of these polypeptides naturally or as a result of cDNA transfection and 2) to determine whether AFGF, BFGF and/or FGF receptor gene expression is modulated during atherosclerotic lesion development and/or during the response of atherosclerotic arteries to balloon injury. These experiments will utilize the New Zealand white rabbit as a model to study atherogenesis and angioplasty-induced restenosis. Although data has accumulated indicating that AFGF and BFGF may play a critical role in SMC growth control, it is not yet known whether any of the signal peptide-containing members of the FGF family could also be important. Thus, the third specific aim of this proposal is to determine whether int-2 or FGF-5, two of the five signal sequence-containing members of the FGF family of polypeptides, warrant consideration as mediators of SMC growth control in vivo. Initial experiments will assay the ability of these proteins to stimulate human SMC proliferation. If they are mitogenic, additional studies examining the regulation of int-2 and FGF-5 gene expression by vascular cells in vitro and in vivo and in vivo will also be initiated. Results obtained from the research program described in this proposal may aid in the rational design of specific therapeutic approaches to the problem of SMC hyperplasia.
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