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.


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.
Yamaoka-Tojo
Minako
M
Division of Cardiology, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, GA 30322, USA.
Tojo
Taiki
T
Kim
Ha Won
HW
Hilenski
Lula
L
Patrushev
Nikolay A
NA
Zhang
Lynn
L
Fukai
Tohru
T
Ushio-Fukai
Masuko
M
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
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