: Vascular smooth muscle cell (VSMC) migration from media to intima and its replication in intima is one of the underlying factors in the pathophysiology of atherosclerosis and restenosis. Several biogenic molecules such as peptide growth factors, cytokines, eicosanoids and oxidants that are generated at the site of arterial injury can trigger the formation of these vascular lesions via stimulating VSMC migration and proliferation. Therefore, elucidating the signal transduction mechanisms that are integral to VSMC migration and proliferation and shared by many of these biogenic molecules may lead to the development of therapeutic agents against these vascular lesions. The preliminary research in our laboratories showed that transcriptional factors namely nuclear factors of activated T cells (NFATs) are present in VSMC. Furthermore, platelet-derived growth factor-BB (PDGFBB) and thrombin, potent VSMC mitogens and chemokines activated NFATs in VSMC. More importantly, cyclosporin A, a potent and specific inhibitor of the NFAT activation pathway, significantly reduced PDGFBB and thrombin-induced DNA synthesis in VSMC. In view of these exciting findings we hypothesize that NFATs play an important role in agonist-induced VSMC migration and proliferation in vitro and injury-induced neointima formation in vivo. To achieve this goal we will propose to address the following four specific aims: 1) To determine the role of NFATs in receptor tyrosine kinase (RTK) and G-protein-coupled receptor (GPCR) agonist-induced VSMC gene expression; 2) To determine the role of NFATs in RTK and GPCR agonist-induced VSMC growth; 3) To study the role of NFATs in VSMC migration in response to RTK and GPCR agonists; and 4) To study the role of NFATs in VSMC growth induction in rat carotid balloon injury model of restenosis. The results of the experiments proposed in this research project will provide novel information with regard to the role of NFATs in the regulation of RTK and GPCR agonist-induced VSMC growth and migration in vitro and in the pathogenesis of injury-induced restenosis.
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