on June 8, 2006
Published online before print June 8, 2006, doi: 10.1161/01.ATV.0000231524.14873.e7
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Submitted on August 3, 2005
Accepted on May 24, 2006
IQGAP1 Mediates VE-Cadherin-Based Cell-Cell Contacts and VEGF Signaling at Adherence Junctions Linked to Angiogenesis
Minako Yamaoka-Tojo ;
From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga.
* To whom correspondence should be addressed. 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 
-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/-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.
Key words: angiogenesis • cell-cell adherions • IQGAP1 • reactive oxygen species • vascular endothelial growth factor • VE-cadherin
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