As a leading cause of restenosis, neointimal hyperplasia is common to small caliber grafting, endarterectomy and balloon angioplasty. Following surgical injury to the arterial wall, activated smooth muscle cells (SMC) migrate and then proliferate in the neointima. The accumulation of SMCs and deposition of extracellular matrix lead to a hemodynamically compromising luminal reduction, which is developed in a fraction of the time needed for the primary atherosclerotic lesion. In addition, the neointima is primarily made up of SMCs while the primary lesion is multicellular and without a dominant cell type. To prevent recurrent stenosis, this rapid accumulation of SMCs in the neointima must be inhibited; however, only minimal information is currently available on the mechanisms of accelerated SMC accumulation in the neointima. Preliminary data for this proposal indicate that migration of SMCs is critical in the development of the neointimal lesion, and the work proposed here focuses on the mechanisms of SMC migration and possible techniques to inhibit it. SMC migration is activated by chemotactic and chemokinetic signals generated following arterial injury and is mediated by interaction of SMC, integrins expressed on the cell surface and the extracellular matrix. This proposal will test the hypotheses that SMC migration can be inhibited by disrupting the actions of those mediators (e.g. growth factors, integrins and extracellular matrix) and, in turn, the neointimal lesion formation can be prevented. The mechanisms of action on the SMC by the activating signals, platelet-derived growth factor and transforming growth factor-beta, will be delineated. The role of integrin receptors (e.g. alpha-v-beta-3) and the extracellular matrix in SMC migration will be examined. To assess cell migration, in vitro and in vivo cell migration assays will be performed. To determine the effect of inhibition of SMC migration on the neointimal lesion formation, animal studies will be performed with the appropriate agonists and antagonists. The results from these studies may provide new and valuable information on the mechanism of SMC migration and inhibition of the neointimal lesion as well as insight into the development of atherosclerosis.
