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

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

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 β-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/β-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.

Original languageEnglish (US)
Pages (from-to)1991-1997
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume26
Issue number9
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

Keywords

  • Angiogenesis
  • Cell-cell adherions
  • IQGAP1
  • Reactive oxygen species
  • VE-cadherin
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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