Activation of integrin receptors is required for growth factor-induced smooth muscle cell dysfunction

Abstract

Purpose: Growth factors and cytokines such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and transforming growth factor beta (TGF) stimulate smooth muscle cell (SMC) proliferation and extracellular matrix (ECM) protein production by binding and activating their respective receptors. Recent investigations suggest that simultaneous activation of integrins, which are heterodimeric receptors for ECM, may also be required for growth factor and cytokine function. In this study, we tested the hypothesis that activation of two integrins, ggavβ3 and α2β1, both previously identified in vascular SMCs, is necessary for growth factor- and cytokine-induced vascular SMC dysfunction.Methods. DNA synthesis was measured after stimulation of SMCs derived from human saphenous vein with the growth factors PDGF-BB, EGF, and bFGF. SMC fibronectin (Fn) production was measured (by means of Western blotting) in SMCs stimulated for 72 hours with TGF-β1 or EGF. Both endpoints were measured in the presence and absence of antibodies that block the function of the αvβ3 and α2β1 integrins as well as the α2 and βl subunits.Results: The αvβ3 integrin blocking antibody significantly inhibited PDGF-BB-, EGF-, and bFGF-induced SMC proliferation. The αvβ3 integrin antibody also markedly inhibited TGF-1- and EGF-induced SMC Fn production. Neither the a2 1 integrin nor the α2 or the β1 subunits inhibited either proliferation or matrix protein production in response to any of these agonists.Conclusion: The αvβ3 integrin is required for growth factor- and cytokine-induced SMC proliferation and FN production, whereas α2β1 is not. Since activation of αvβ3 is required for the activity of at least four distinct growth factors and cytokines, inhibition of this integrin might be used as a therapeutic tool for the prevention of intimal hyperplasia.