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(Circulation Research. 2002;91:1160.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Novel Role of gp91^phox-Containing NAD(P)H Oxidase in Vascular Endothelial Growth Factor–Induced Signaling and Angiogenesis

Masuko Ushio-Fukai, Yan Tang, Tohru Fukai, Sergey I. Dikalov, Yuxian Ma, Mitsuaki Fujimoto, Mark T. Quinn, Patrick J. Pagano, Chad Johnson, R. Wayne Alexander

From the Division of Cardiology, Department of Medicine (M.U.-F., Y.T., T.F., S.I.D., Y.M., M.F., C.J., R.W.A.), Emory University School of Medicine, Atlanta, Ga; the Department of Veterinary Molecular Biology (M.T.Q.), Montana State University, Bozeman, Mont; and Hypertension and Vascular Research Division (P.J.P.), Henry Ford Hospital, Detroit, Mich.

Correspondence to Masuko Ushio-Fukai, PhD, Division of Cardiology, Emory University School of Medicine, 1639 Pierce Dr, Rm 319, Atlanta, GA 30322. E-mail mfukai{at}emory.edu

Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating endothelial cell proliferation and migration, primarily through the receptor tyrosine kinase VEGF receptor2 (Flk1/KDR). Reactive oxygen species (ROS) derived from NAD(P)H oxidase are critically important in many aspects of vascular cell regulation, and both the small GTPase Rac1 and gp91^phox are critical components of the endothelial NAD(P)H oxidase complex. A role of NAD(P)H oxidase in VEGF-induced angiogenesis, however, has not been defined. In the present study, electron spin resonance spectroscopy is utilized to demonstrate that VEGF stimulates O₂^·- production, which is inhibited by the NAD(P)H oxidase inhibitor, diphenylene iodonium, as well as by overexpression of dominant-negative Rac1 (N17Rac1) and transfection of gp91^phox antisense oligonucleotides in human umbilical vein endothelial cells (ECs). Antioxidants, including N-acetylcysteine (NAC), various NAD(P)H oxidase inhibitors, and N17Rac1 significantly attenuate not only VEGF-induced KDR tyrosine phosphorylation but also proliferation and migration of ECs. Importantly, these effects of VEGF are dramatically inhibited in cells transfected with gp91^phox antisense oligonucleotides. By contrast, ROS are not involved in mediating these effects of sphingosine 1-phosphate (S1P) on ECs. Sponge implant assays demonstrate that VEGF-, but not S1P-, induced angiogenesis is significantly reduced in wild-type mice treated with NAC and in gp91^phox-/- mice, suggesting that ROS derived from gp91^phox-containing NAD(P)H oxidase play an important role in angiogenesis in vivo. These studies indicate that VEGF-induced endothelial cell signaling and angiogenesis is tightly controlled by the reduction/oxidation environment at the level of VEGF receptor and provide novel insights into the NAD(P)H oxidase as a potential therapeutic target for angiogenesis-dependent diseases.

Key Words: NAD(P)H oxidase • reactive oxygen species • vascular endothelial growth factor • angiogenesis • endothelial cells

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				L. Zuo, M. Ushio-Fukai, L. L. Hilenski, and R. W. Alexander Microtubules Regulate Angiotensin II Type 1 Receptor and Rac1 Localization in Caveolae/Lipid Rafts: Role in Redox Signaling Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1223 - 1228. [Abstract] [Full Text] [PDF]

				J. F. Wang, X. Zhang, and J. E. Groopman Activation of Vascular Endothelial Growth Factor Receptor-3 and Its Downstream Signaling Promote Cell Survival under Oxidative Stress J. Biol. Chem., June 25, 2004; 279(26): 27088 - 27097. [Abstract] [Full Text] [PDF]

				J. C. Mamputu and G. Renier Advanced glycation end-products increase monocyte adhesion to retinal endothelial cells through vascular endothelial growth factor-induced ICAM-1 expression: inhibitory effect of antioxidants J. Leukoc. Biol., June 1, 2004; 75(6): 1062 - 1069. [Abstract] [Full Text] [PDF]

				T. Tanimoto, A. O. Lungu, and B. C. Berk Sphingosine 1-Phosphate Transactivates the Platelet-Derived Growth Factor {beta} Receptor and Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells Circ. Res., April 30, 2004; 94(8): 1050 - 1058. [Abstract] [Full Text] [PDF]

				M. Z. Haque and D. S. A. Majid Assessment of Renal Functional Phenotype in Mice Lacking gp91PHOX Subunit of NAD(P)H Oxidase Hypertension, February 1, 2004; 43(2): 335 - 340. [Abstract] [Full Text] [PDF]

				R. S. Frey and A. B. Malik Oxidant signaling in lung cells Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L1 - L3. [Full Text] [PDF]

				Y. Taniyama and K. K. Griendling Reactive Oxygen Species in the Vasculature: Molecular and Cellular Mechanisms Hypertension, December 1, 2003; 42(6): 1075 - 1081. [Abstract] [Full Text] [PDF]

				M.-T. Lin, M.-L. Yen, C.-Y. Lin, and M.-L. Kuo Inhibition of Vascular Endothelial Growth Factor-Induced Angiogenesis by Resveratrol through Interruption of Src-Dependent Vascular Endothelial Cadherin Tyrosine Phosphorylation Mol. Pharmacol., November 1, 2003; 64(5): 1029 - 1036. [Abstract] [Full Text] [PDF]

				D. Saha, K. R. Sekhar, C. Cao, J. D. Morrow, H. Choy, and M. L. Freeman The Antiangiogenic Agent SU5416 Down-Regulates Phorbol Ester-Mediated Induction of Cyclooxygenase 2 Expression by Inhibiting Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activity Cancer Res., October 15, 2003; 63(20): 6920 - 6927. [Abstract] [Full Text] [PDF]

				R. F. Wu, Y. Gu, Y. C. Xu, F. E. Nwariaku, and L. S. Terada Vascular Endothelial Growth Factor Causes Translocation of p47phox to Membrane Ruffles through WAVE1 J. Biol. Chem., September 19, 2003; 278(38): 36830 - 36840. [Abstract] [Full Text] [PDF]

				X. Bai, F. Cerimele, M. Ushio-Fukai, M. Waqas, P. M. Campbell, B. Govindarajan, C. J. Der, T. Battle, D. A. Frank, K. Ye, et al. Honokiol, a Small Molecular Weight Natural Product, Inhibits Angiogenesis in Vitro and Tumor Growth in Vivo J. Biol. Chem., September 12, 2003; 278(37): 35501 - 35507. [Abstract] [Full Text] [PDF]

				J. A. Leopold, J. Walker, A. W. Scribner, B. Voetsch, Y.-Y. Zhang, A. J. Loscalzo, R. C. Stanton, and J. Loscalzo Glucose-6-phosphate Dehydrogenase Modulates Vascular Endothelial Growth Factor-mediated Angiogenesis J. Biol. Chem., August 22, 2003; 278(34): 32100 - 32106. [Abstract] [Full Text] [PDF]

				B. Lassegue and R. E. Clempus Vascular NAD(P)H oxidases: specific features, expression, and regulation Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R277 - R297. [Abstract] [Full Text] [PDF]

				R. Tamarat, J.-S. Silvestre, M. Huijberts, J. Benessiano, T. G. Ebrahimian, M. Duriez, M.-P. Wautier, J. L. Wautier, and B. I. Levy Blockade of advanced glycation end-product formation restores ischemia-induced angiogenesis in diabetic mice PNAS, July 8, 2003; 100(14): 8555 - 8560. [Abstract] [Full Text] [PDF]

				D. G Harrison, Hua Cai, U. Landmesser, and K. K Griendling The Pickering Lecture British Hypertension Society, 10th September 2002: Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, June 1, 2003; 4(2): 51 - 61. [Abstract] [PDF]

				M. E. Cifuentes and P. J. Pagano c-Src and Smooth Muscle NAD(P)H Oxidase: Assembling a Path to Hypertrophy Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 919 - 921. [Full Text] [PDF]

				E. L. Schiffrin and R. M. Touyz Inflammation and Vascular Hypertrophy Induced by Angiotensin II: Role of NADPH Oxidase-Derived Reactive Oxygen Species Independently of Blood Pressure Elevation? Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 707 - 709. [Full Text] [PDF]

				R. P. Brandes A Radical Adventure: The Quest for Specific Functions and Inhibitors of Vascular NAPDH Oxidases Circ. Res., April 4, 2003; 92(6): 583 - 585. [Full Text] [PDF]