title: IQGAP1 mediates VE-cadherin-based cell-cell contacts and VEGF signaling at adherence junctions linked to angiogenesis.
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 beta-catenin, thereby regulating cell motility and morphogenesis.
  
  
  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.
authors.affiliation: Division of Cardiology, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, GA 30322, USA.
authors.forename: Minako
authors.initials: M
authors.lastname: Yamaoka-Tojo
authors.forename: Taiki
authors.initials: T
authors.lastname: Tojo
authors.forename: Ha Won
authors.initials: HW
authors.lastname: Kim
authors.forename: Lula
authors.initials: L
authors.lastname: Hilenski
authors.forename: Nikolay A
authors.initials: NA
authors.lastname: Patrushev
authors.forename: Lynn
authors.initials: L
authors.lastname: Zhang
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukai
authors.forename: Masuko
authors.initials: M
authors.lastname: Ushio-Fukai
mesh_terms: D022005:Adherens Junctions / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000502:physiology*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D017382:Reactive Oxygen Species; D014443:Tyrosine; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D051176:beta Catenin; D020703:ras GTPase-Activating Proteins; D000099152:Cadherin 5; C101203:IQ motif containing GTPase activating protein 1