MECHANISM OF CATECHOLAMINE-INDUCED PROLIFERATION OF VASCULAR SMOOTH-MUSCLE CELLS

Background Catecholamines have been shown to aggravate atherosclerosis in animals and humans, and abnormal proliferation of vascular smooth muscle cells (VSMC) is a key event in the early stage of atheroscleros is. Catecholamines may be involved in such cell growth. Therefore, a s eries of experiments using cultured VSMC was performed to elucidate th eir possible mitogenic effect. Methods and Results We examined the mit ogenic effect of catecholamines using rat aortic smooth muscle cells ( VSMC) by measuring [H-3]thymidine incorporation, checking with flow cy tometry, and counting the cell number directly. Furthermore, the catec holamine-activated signal transduction pathway was assessed by measure ment of the formation of inositol I, 4,5-triphosphate, intracellular C a2+ concentration, mitogen-activated protein kinase (MAPK) activity, a nd mitogenic gene expression. Norepinephrine (NE) and phenylephrine st imulated [H-3]thymidine incorporation and cell growth. Clonidine and i soproterenol showed little of such effects. Prazosin was more effectiv e than either yohimbine or propranolol in suppressing the mitogenic ef fect of NE, indicating that catecholamine-induced VSMC proliferation i s mediated by alpha(1)-adrenoceptors. The alpha(1)-adrenoceptor activa tion was coupled to pertussis toxin-insensitive G(q)-protein and trigg ered phosphoinositide hydrolysis with subsequent activation of protein kinase C and MAPK in VSMC. In response to NE, both 42- and 44-kD MAPK were activated and tyrosine was phosphorylated. alpha(1)-Adrenoceptor stimulation with NE also caused accumulation of c-fos, c-jun, and c-m yc mRNA. Chloroethylclonidine completely blocked the alpha(1)-adrenoce ptor-mediated mitogenesis. Conclusions The effect of catecholamines ap pears to be mediated via the activation of the chloroethylclonidine-se nsitive alpha(1)-adrenoceptors that triggers the phosphoinositide hydr olysis and activates the MAPK pathway, leading to DNA synthesis and ce ll proliferation.