Control of smooth muscle cell proliferation and phenotype by integrin signaling through focal adhesion kinase

Extracellular matrix proteins such as fibronectin (FN) and laminin (LM) are known to help control the growth and phenotype of vascular smooth muscle c ells (VSMCs). Here we have analyzed the relationship between growth factor and integrin signaling pathways in VSMCs. Culturing porcine coronary artery smooth muscle cells (PCASMCs) on FN and LM leads to distinct effects on ce ll proliferation and contractile protein expression. PCASMCs cultured on FN proliferate at a higher rate than cells cultured on LM, regardless of the growth factor used to support proliferation. Moreover, cells cultured on LM show higher levels of expression of smooth muscle myosin heavy chain (a ma rker of smooth muscle cell differentiation) than cells cultured on FN. In c ontrast to the effects on proliferation and contractile protein expression, both FN and LM supported cell migration in response to PDGF. Also, both FN and LM supported activation of ERK1 and ERK2 in response to PDGF and bFGF. However, FN and LM did show a difference in their ability to support signa ling through the focal adhesion kinase (FAK). PCASMCs cultured on FN show r obust activation of FAK in response to either PDGF or bFGF, however, cells cultured on LM show little-to-no activation of FAK in response to the growt h factors. The results show that integrin signaling pathways have a profoun d effect on VSMC proliferation and phenotype, and that FAB is an important intermediate in these signaling pathways. The implications of our findings on the mechanisms controlling VSMC proliferation and phenotype in pathologi cal states such as atherosclerosis and restenosis are discussed. (C) 2000 A cademic Press.