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Am J Physiol Cell Physiol 285: C1330-C1338, 2003. First published July 23, 2003; doi:10.1152/ajpcell.00475.2002
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VASCULAR BIOLOGY

{alpha}v{beta}3-Integrin antagonists inhibit thrombin-induced proliferation and focal adhesion formation in smooth muscle cells

M. Sajid, R. Zhao, A. Pathak, S. S. Smyth, and G. A. Stouffer

Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina 27599

Submitted 10 October 2002 ; accepted in final form 10 July 2003

{alpha}v{beta}3-Integrin antagonists reduced neointimal formation following vascular injury in eight different animal models. Because {alpha}-thrombin contributes to neointimal formation, we examined the hypothesis that {alpha}v{beta}3-integrins influence {alpha}-thrombin-induced signaling. Cultured rat aortic smooth muscle cells (RASMC) expressed {alpha}v{beta}3-integrins as demonstrated by immunofluorescence microscopy and fluorescence-activated cell sorting analysis. Proliferative responses to {alpha}-thrombin were partially inhibited by anti-{beta}3-integrin monoclonal antibody F11 and by cyclic RGD peptides. Immunofluorescence microscopy showed that {alpha}-thrombin stimulated a rapid increase in the formation of focal adhesions as identified by vinculin staining and that this effect was partially inhibited by {alpha}v{beta}3 antagonists. {beta}3-Integrin staining was diffuse in quiescent RASMC and did not concentrate at sites of focal adhesions following thrombin treatment. {alpha}-Thrombin elicited a time-dependent increase in activation of c-Jun NH2-terminal kinase-1 (JNK1) and in tyrosine phosphorylation of focal adhesion kinase (FAK). {alpha}v{beta}3-Integrin antagonists partially inhibited increases in JNK1 activity but had no effect on FAK phosphorylation. In SMC isolated from {beta}3-integrin-deficient mice, focal adhesion formation was impaired in response to thrombin but not sphingosine-1-phosphate, a potent activator of Rho. In summary, {alpha}v{beta}3-integrins play an important role in {alpha}-thrombin-induced proliferation and focal adhesion formation in RASMC.

receptors; vitronectin; integrins; focal adhesions


Address for reprint requests and other correspondence: G. A. Stouffer, Division of Cardiology, Univ. of North Carolina, Chapel Hill, NC 27599-7075 (E-mail: rstouff{at}med.unc.edu).




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