Abnormal vascular smooth muscle cell (SMC) growth and migration contributes to hypertension, atherosclerosis, and restenosis. SMC function is controlled by complex regulatory mechanisms, which are governed in part by interactions with the extracellular matrix. Integrins, the predominant receptors for the extracellular matrix, activate adhesion-dependent signaling pathways and cross-talk with growth factor and G-protein coupled receptors to influence cellular functions. The objective of this application is to understand how integrin alphaVbeta3-dependent signaling influences SMC growth and migration. We observed that wild-type mice treated with an antibody-inhibitor of beta3-integrins, but not beta3-integrin-deficient (beta3-/-) mice, were protected from the development of intimal hyperplasia and have found differences in the properties of cultured wild-type and beta3-/- SMCs that may account for our in vivo observations. Based on our preliminary data, we hypothesize that integrin alphaVbeta3- dependent intracellular signaling positively and negatively regulates SMC growth and migration thorugh distinct pathways in stimulated and quiescent SMCs. The proposed studies will utilize genetic, pharmacologic, and RNA interference techniques to target integrin alphaVbeta3 in well-characterized cellular and animal models of SMC function. First, we will identify alphaVbeta3-dependent pathways in stimulated SMCs. Our preliminary data indicates that alphaVbeta3 serves as a molecular switch to regulate Rho Family GTPase and control focal adhesion assembly. We will delineate the mechanism(s) responsible for GTPase regulation. Second, based on our preliminary data, we have identified a role for alphaVbeta3 in downregulation of p38MAPK during cellular quiescence. We will use the p38 MAPK pathway as a model to understand how alphaVbeta3-dependent pathways contribute to SMC quiescence. Third, we will delineate the contribution of alphaVbeta3 to physiologic responses in cultured vessels and well-established mouse models of arterial injury. These results will provide specific insights into the function of SMC alphaVbeta3 in restenosis and atherosclerosis and may have broad implications for understanding alphaVbeta3 integrin function in angiogenesis, osteoporosis, and other disorders.
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