HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 48, 35373-35385, November 30, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/48/35373    most recent M702175200v2 M702175200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Abid, Md. R. Articles by Aird, W. C. Search for Related Content PubMed PubMed Citation Articles by Abid, Md. R. Articles by Aird, W. C. Social Bookmarking                      What's this?

NADPH Oxidase Activity Selectively Modulates Vascular Endothelial Growth Factor Signaling Pathways^*

Md. Ruhul Abid¹, Katherine C. Spokes, Shou-Ching Shih, and William C. Aird

From the Division of Molecular and Vascular Medicine, Department of Medicine and Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) play critical roles in vascular physiology and pathophysiology. We have demonstrated previously that NADPH oxidase-derived ROS are required for VEGF-mediated migration and proliferation of endothelial cells. The goal of this study was to determine the extent to which VEGF signaling is coupled to NADPH oxidase activity. Human umbilical vein endothelial cells and/or human coronary artery endothelial cells were transfected with short interfering RNA against the p47^phox subunit of NADPH oxidase, treated in the absence or presence of VEGF, and assayed for signaling, gene expression, and function. We show that NADPH oxidase activity is required for VEGF activation of phosphoinositide 3-kinase-Akt-forkhead, and p38 MAPK, but not ERK1/2 or JNK. The permissive role of NADPH oxidase on phosphoinositide 3-kinase-Akt-forkhead signaling is mediated at post-VEGF receptor levels and involves the nonreceptor tyrosine kinase Src. DNA microarrays revealed the existence of two distinct classes of VEGF-responsive genes, one that is ROS-dependent and another that is independent of ROS levels. VEGF-induced, thrombomodulin-dependent activation of protein C was dependent on NADPH oxidase activity, whereas VEGF-induced decay-accelerating factor-mediated protection of endothelial cells against complement-mediated lysis was not. Taken together, these findings suggest that NADPH oxidase-derived ROS selectively modulate some but not all the effects of VEGF on endothelial cell phenotypes.

Received for publication, March 13, 2007 , and in revised form, September 24, 2007.

^* This work was supported by American Heart Association Grant SDG 0453284N and National Institutes of Health Grants 5R01HL077348 and 5R01HL082927. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-5.

¹ To whom correspondence should be addressed: Molecular and Vascular Medicine, Dept. of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, E/RW-663, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-1025; Fax: 617-667-2913; E-mail: rabid{at}bidmc.harvard.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				N. Urao, H. Inomata, M. Razvi, H. W. Kim, K. Wary, R. McKinney, T. Fukai, and M. Ushio-Fukai Role of Nox2-Based NADPH Oxidase in Bone Marrow and Progenitor Cell Function Involved in Neovascularization Induced by Hindlimb Ischemia Circ. Res., July 18, 2008; 103(2): 212 - 220. [Abstract] [Full Text] [PDF]

				K. Mahadev, X. Wu, S. Donnelly, R. Ouedraogo, A. D. Eckhart, and B. J. Goldstein Adiponectin inhibits vascular endothelial growth factor-induced migration of human coronary artery endothelial cells Cardiovasc Res, May 1, 2008; 78(2): 376 - 384. [Abstract] [Full Text] [PDF]