IQGAP1 mediates VE-cadherin-based cell-cell contacts and VEGF signaling at adherence junctions linked to angiogenesis

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 beta- 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/ beta- 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.