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Blood, 15 November 2004, Vol. 104, No. 10, pp. 3214-3220. Prepublished online as a Blood First Edition Paper on July 22, 2004; DOI 10.1182/blood-2004-05-1868. This Article Full Text (PDF) All Versions of this Article: 2004-05-1868v1 104/10/3214    most recent Alert me when this article is cited Alert me if a correction is posted 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nwariaku, F. E Articles by Terada, L. S Search for Related Content PubMed PubMed Citation Articles by Nwariaku, F. E Articles by Terada, L. S Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 17, 2004 Accepted July 2, 2004 The NADPH Oxidase Mediates Vascular Endothelial Cadherin Phosphorylation and Endothelial Dysfunction Fiemu E Nwariaku*, Zijuan Liu, Xudong Zhu, Dorit Nahari, Christine Ingle, Ru Feng Wu, Ying Gu, George Sarosi, and Lance S Terada Departments of Surgery and Pulmonary Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Dallas VA Medical Center, Dallas, Texas, USA Departments of Surgery and Pulmonary Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA Dallas VA Medical Center, Dallas, Texas, USA * Corresponding author; email: fiemu.nwariaku{at}utsouthwestern.edu. Vascular endothelial activation is an early step during leukocyte endothelial adhesion and trans endothelial leukocyte migration in inflammatory states. Leukocyte transmigration occurs through intercellular gaps between endothelial cells. Vascular endothelial cadherin, VE cadherin is a predominant component of endothelial adherens junctions and regulates intercellular gap formation. We found that tumor necrosis factor (TNF) caused tyrosine phosphorylation of VE cadherin, separation of lateral cell-cell junctions and intercellular gap formation in human umbilical vein endothelial cells (HUVEC) monolayers. These events appear to be regulated by intracellular oxidant production via the endothelial NADPH oxidase, because both antioxidants and expression of a transdominant inhibitor of the NADPH oxidase, p67(V204A), effectively blocked the effects of TNF on all three of these parameters of junctional integrity. Antioxidants and p67(V204A) also decreased TNF-induced JNK activation; and dominant negative JNK abrogated VE-cadherin phosphorylation and junctional separation, suggesting a downstream role for JNK. Finally, adenoviral delivery of the kinase dead PAK1,(K298A) decreased TNF-induced JNK activation, VE-cadherin phosphorylation and lateral junctional separation; consistent with the proposed involvement of PAK1 upstream of the NADPH oxidase. Thus PAK-1 acts in concert with the oxidase during TNF induced oxidant production and loss of endothelial cell junctional integrity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Gianni, B. Diaz, N. Taulet, B. Fowler, S. A. Courtneidge, and G. M. Bokoch Novel p47phox-Related Organizers Regulate Localized NADPH Oxidase 1 (Nox1) Activity Sci. Signal., September 15, 2009; 2(88): ra54 - ra54. [Abstract] [Full Text] [PDF] S. J. Mathew, D. Haubert, M. Kronke, and M. Leptin Looking beyond death: a morphogenetic role for the TNF signalling pathway J. Cell Sci., June 15, 2009; 122(12): 1939 - 1946. [Abstract] [Full Text] [PDF] K. S. Farley, L. Wang, and S. 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Satchi-Fainaro, M. Chen, I. Mitchell, L. B. Task, Z. Liu, J. Kihneman, A. B. Carroll, L. S. Terada, and F. E. Nwariaku Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer Mol. Cancer Ther., April 1, 2007; 6(4): 1329 - 1337. [Abstract] [Full Text] [PDF] D. M. Shasby Cell-cell adhesion in lung endothelium Am J Physiol Lung Cell Mol Physiol, March 1, 2007; 292(3): L593 - L607. [Abstract] [Full Text] [PDF] A. Sakurai, S. Fukuhara, A. Yamagishi, K. Sako, Y. Kamioka, M. Masuda, Y. Nakaoka, and N. Mochizuki MAGI-1 Is Required for Rap1 Activation upon Cell-Cell Contact and for Enhancement of Vascular Endothelial Cadherin-mediated Cell Adhesion Mol. Biol. Cell, February 1, 2006; 17(2): 966 - 976. [Abstract] [Full Text] [PDF] N. Lambeng, Y. Wallez, C. Rampon, F. Cand, G. Christe, D. Gulino-Debrac, I. Vilgrain, and P. Huber Vascular Endothelial-Cadherin Tyrosine Phosphorylation in Angiogenic and Quiescent Adult Tissues Circ. 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