Published online before print June 8, 2006, doi: 10.1161/01.ATV.0000231524.14873.e7
© 2006 American Heart Association, Inc.
Vascular Biology |
IQGAP1 Mediates VE-Cadherin–Based Cell–Cell Contacts and VEGF Signaling at Adherence Junctions Linked to Angiogenesis
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
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