Vascular endothelial growth factor induces manganese‐superoxide dismutase expression in endothelial cells by a Racl‐regulated NADPH oxidase‐dependent mechanism

Vascular endothelial growth factor (VEGF) is a potent vascular endothelial cell‐specific mitogen that modulates endothelial cell function. In the present study, we show that VEGF induces manganese‐superoxide dismutase (MnSOD) mRNA and protein in human coronary artery endothelial cells (HCAEC) and pulmonary artery endothelial cells. VEGF‐mediated induction of MnSOD mRNA was inhibited by pretreatment with the NADPH oxidase inhibitors, diphenyleneiodonium (DPI), and 4‐(2‐aminoethyl)‐benzenesulfonyl fluoride, but not with the nitric oxide synthase inhibitor L‐NAME (N‐monomethyl‐L‐arginine) or the xanthine oxidase inhibitor allopurinol. VEGF stimulation of MnSOD was also inhibited by adenoviral‐mediated overexpression of catalase Cu, Zn‐SOD and a dominant‐negative form of the small GTPase component of NADPH oxidase Rac1 (Rac1N17). Treatment of HCAEC with VEGF resulted in a transient increase in ROS production at 20 min, as measured by 2′,7′‐dichlorodihydrofluorescein oxidation. This effect was abrogated by expression of Rac1N 17. Taken together, these findings suggest that VEGF induces MnSOD by an NADPH oxidase‐dependent mechanism and that VEGF signaling in the endothelium is coupled to the redox state of the cell.