Reactive oxygen and NF-κB in VEGF-induced migration of human vascular smooth muscle cells

Migration and proliferation of vascular smooth muscle cells (VSMC) contribute to angiogenesis and the lesions of atherosclerosis. Since, vascular endothelial growth factor (VEGF) is overexpressed by VSMC in intima of atherosclerotic human coronary arteries, we determined if VEGF could stimulate VSMC migration and the intracellular signals involved. VEGF induced VSMC migration but had no significant activity on proliferation. VEGF increased intracellular reactive oxygen species (RES), NF-κB activation and IL-6 expression. Blockade of the generation of intracellular ROS by antioxidants inhibited VEGF-induced NF-κB activation, IL-6 expression, and cell migration indicating that generation of Res was required for NF-κB activation and the chemotactic activity of VEGF. Expression of a mutated, nondegradable form of inhibitor of NF-κB (IκB-αM) suppressed VEGF-triggered activation of NF-κB and upregulation of IL-6 as well as VSMC migration. Neutralization of IL-6 by its antibody significantly attenuated the migration stimulated by VEGF. Collectively, our data provide the first evidence that intracellular Res and NF-κB are required for VEGF-mediated smooth muscle cell migration. Further, IL-6 induced by VEGF is involved in the ability of the growth factor to stimulate migration.