Smooth muscle cell (SMC) proliferation is an important cause of intimal thickening and luminal stenosis in damaged arteries and vascular grafts. Intimal thickening is stimulated by injury and is more pronounced in the presence of low blood flow. It is inhibited by treatment with heparin. The principal objective of this proposal is to investigate how blood flow and heparin regulate endothelial and SMC growth in a baboon aortoiliac polytetrafluoroethylene (PTFE) graft model of intimal hyperplasia. A secondary objective will be to determine if SMC seeded into grafts can be used as a stable delivery system for gene therapy. In the baboon PTFE graft model, a thin neointima is established in the presence of increased blood flow (produced by a small distal arteriovenous fistula). Closure of the fistula restores normal blood flow in the graft and stimulates a five fold increase in intimal thickening within one month. We propose to define the time course of intimal cell proliferation, the dependence of the thickening process on the presence of endothelium, and the relationship between cell proliferation and growth factor gene expression (PDGF, basic FGF). We will then determine if heparin inhibits SMC proliferation and neointimal thickening. In addition, we will explore the possibility that genetically modified baboon SMC seeded into grafts or deendothelialized arteries are good vectors for delivering genes of therapeutic importance. These studies are of potential clinical interest since they may provide new insights into mechanisms of SMC growth and the control of vascular structure in response to physiological stimuli such as altered blood flow. In addition, they may help to provide the basis for a clinically useful approach to gene therapy.
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