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

Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):1991-7. doi: 10.1161/01.ATV.0000231524.14873.e7. Epub 2006 Jun 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adherens Junctions / physiology*
  • Animals
  • Antigens, CD
  • Cadherins / physiology*
  • Cell Communication / physiology*
  • Cells, Cultured
  • Hindlimb / blood supply
  • Humans
  • Ischemia / metabolism
  • Ischemia / physiopathology
  • Mice
  • Neovascularization, Physiologic / physiology*
  • Phosphorylation
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / physiology*
  • Subcellular Fractions / metabolism
  • Tissue Distribution
  • Tyrosine / metabolism
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • beta Catenin / metabolism
  • ras GTPase-Activating Proteins / physiology*


  • Antigens, CD
  • Cadherins
  • IQ motif containing GTPase activating protein 1
  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A
  • beta Catenin
  • cadherin 5
  • ras GTPase-Activating Proteins
  • Tyrosine
  • Vascular Endothelial Growth Factor Receptor-2