This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 26/9/1991    most recent 01.ATV.0000231524.14873.e7v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamaoka-Tojo, M. Articles by Ushio-Fukai, M. Search for Related Content PubMed PubMed Citation Articles by Yamaoka-Tojo, M. Articles by Ushio-Fukai, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB L-TYROSINE

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1991.)
© 2006 American Heart Association, Inc.

Vascular Biology

IQGAP1 Mediates VE-Cadherin–Based Cell–Cell Contacts and VEGF Signaling at Adherence Junctions Linked to Angiogenesis

Minako Yamaoka-Tojo; Taiki Tojo; Ha Won Kim; Lula Hilenski; Nikolay A. Patrushev; Lynn Zhang; Tohru Fukai; Masuko Ushio-Fukai

From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga.

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

Objective— Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating reactive oxygen species (ROS) production primarily through the VEGF receptor-2 (VEGFR2). One of the initial responses in established vessels to stimulate angiogenesis is loss of vascular endothelial (VE)-cadherin–based cell–cell adhesions; however, little is known about the underlying mechanisms. IQGAP1 is a novel VEGFR2 binding protein, and it interacts directly with actin, cadherin, and ß-catenin, thereby regulating cell motility and morphogenesis.

Methods and Results— Confocal microscopy analysis shows that IQGAP1 colocalizes with VE-cadherin at cell–cell contacts in unstimulated human endothelial cells (ECs). VEGF stimulation reduces staining of IQGAP1 and VE-cadherin at the adherens junction without affecting interaction of these proteins. Knockdown of IQGAP1 using siRNA inhibits localization of VE-cadherin at cell–cell contacts, VEGF-stimulated recruitment of VEGFR2 to the VE-cadherin/ß-catenin complex, ROS-dependent tyrosine phosphorylation of VE-cadherin, which is required for loss of cell–cell contacts and capillary tube formation. IQGAP1 expression is increased in a mouse hindlimb ischemia model of angiogenesis.

Conclusions— IQGAP1 is required for establishment of cell–cell contacts in quiescent ECs. To induce angiogenesis, it may function to link VEGFR2 to the VE-cadherin containing adherens junctions, thereby promoting VEGF-stimulated, ROS-dependent tyrosine phosphorylation of VE-cadherin and loss of cell–cell contacts.

The present study demonstrates that IQGAP1 is required for establishment of basal cell–cell contacts in endothelial cells. It may also function to link VEGF receptor2 to the adherens junctions, thereby promoting reactive oxygen species-dependent tyrosine phoshorylation of VE-cadherin and loss of cell–cell contacts during VEGF-induced angiogenesis.

Key Words: angiogenesis • cell–cell adherions • IQGAP1 • reactive oxygen species • vascular endothelial growth factor • VE-cadherin

This article has been cited by other articles:

				P. V. Usatyuk, I. A. Gorshkova, D. He, Y. Zhao, S. K. Kalari, J. G. N. Garcia, and V. Natarajan Phospholipase D-mediated Activation of IQGAP1 through Rac1 Regulates Hyperoxia-induced p47phox Translocation and Reactive Oxygen Species Generation in Lung Endothelial Cells J. Biol. Chem., May 29, 2009; 284(22): 15339 - 15352. [Abstract] [Full Text] [PDF]

				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]

				Y. Nakamura, N. Patrushev, H. Inomata, D. Mehta, N. Urao, H. W. Kim, M. Razvi, V. Kini, K. Mahadev, B. J. Goldstein, et al. Role of Protein Tyrosine Phosphatase 1B in Vascular Endothelial Growth Factor Signaling and Cell-Cell Adhesions in Endothelial Cells Circ. Res., May 23, 2008; 102(10): 1182 - 1191. [Abstract] [Full Text] [PDF]

				C. H. Ha, A. M. Bennett, and Z.-G. Jin A Novel Role of Vascular Endothelial Cadherin in Modulating c-Src Activation and Downstream Signaling of Vascular Endothelial Growth Factor J. Biol. Chem., March 14, 2008; 283(11): 7261 - 7270. [Abstract] [Full Text] [PDF]

				D. Vestweber VE-Cadherin: The Major Endothelial Adhesion Molecule Controlling Cellular Junctions and Blood Vessel Formation Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 223 - 232. [Abstract] [Full Text] [PDF]