Reactive oxygen and NF-kappa B in VEGF-induced migration of human vascularsmooth muscle cells

Migration and proliferation of vascular smooth muscle cells (VSMC) contribu te to angiogenesis and the lesions of atherosclerosis. Since, vascular endo thelial growth factor (VEGF) is overexpressed by VSMC in intima of atherosc lerotic human coronary arteries, we determined if VEGF could stimulate VSMC migration and the intracellular signals involved. VEGF induced VSMC migrat ion but had no significant activity on proliferation. VEGF increased intrac ellular reactive oxygen species (ROS), NF-kappaB activation and IL-6 expres sion. Blockade of the generation of intracellular ROS by antioxidants inhib ited VEGF-induced NF-kappaB activation, IL-6 expression, and cell migration indicating that generation of ROS was required for NF-kappaB activation an d the chemotactic activity of VEGF. Expression of a mutated, nondegradable form of inhibitor of NF-kappaB (I epsilonB-alphaM) suppressed VEGF-triggere d activation of NF-kappaB and upregulation of IL-6 as well as VSMC migratio n. Neutralization of IL-6 by its antibody significantly attenuated the migr ation stimulated by VEGF. Collectively, our data provide the first evidence that intracellular ROS and NF-kappaB are required for VEGF-mediated smooth muscle cell migration. Further, IL-6 induced by VEGF is involved in the ab ility of the growth factor to stimulate migration. (C) 2001 Academic Press.