Endothelial cell (EC) migration is a key event for endothelial wound repair and angiogenesis. VEGF is a potent stimulator for EC migration primarily through the VEGF type2 receptor (VEGFR2). In quiescent ECs, one of the initial responses to stimulate endothelial migration by VEGF is the loosening of stable cell-cell contacts which is regulated by tyrosine phosphorylation of VE-cadherin. We showed that VEGF stimulates Rac1-dependent gp91phox-based NAD(P)H oxidase and that reactive oxygen species (ROS) are involved in VEGFR2-mediated signaling linked to EC migration. Underlying molecular mechanisms are poorly understood. We recently identified IQGAP1 as a novel VEGFR2 binding protein. It functions as a scaffold protein that controls cell motility and morphogenesis by interacting with cytoskeletal and cell-cell adhesion proteins including active Rac1 and E-cadherin. We also found that: 1) IQGAP1 expression is increased in the newly-formed capillary ECs in a mouse hindlimb ischemia model of angiogenesis;2) Overexpression of IQGAP1 increases basal Rac1 activity, ROS production and cell migration in ECs;3) VEGF promotes recruitment of activated VEGFR2 and Rac1 to the IQGAP1-VE-cadherin complex at adherens junctions, which may promote ROS-dependent loss of cell-cell contacts and subsequent EC migration;4) Wound assays reveal that IQGAP1 colocalizes with active VEGFR2 and gp91phox at the leading edge inactively migrating ECs. We thus hypothesize that IQGAP1 functions as a VEGFR2 binding scaffold protein to link ROS-dependent signaling with VEGF-mediated endothelial migration.
Aim1 will examine whether IQGAP1 functionally interacts with VEGFR2 and Rac1 to couple VEGFR2 to ROS-dependent signaling linked to EC migration.
Aim2 will examine whether IQGAP1 functions as a scaffold to recruit activated VEGFR2 and Rac1 to adherens junctions through binding to VE-cadherin, thereby facilitating ROS-dependent loss of cell-cell contacts, which initiates EC migration.
Aim3 will examine the scaffolding role of IQGAP1 in targeting VEGFR2 and NAD(P)H oxidase to the leading edge during directed cell migration.
Aim4 will assess the functional significance of IQGAP1 in vivo using mouse hindlimb ishcemia model. The long-term goal is to understand the molecular mechanisms by which ROS regulate EC migration in the context of angiogenesis and endothelial wound repair, which should facilitate the development of new therapeutic strategies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Schwartz, Lisa
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University of Illinois at Chicago
Schools of Medicine
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Kim, Young-Mee; Kim, Seok-Jo; Tatsunami, Ryosuke et al. (2017) ROS-induced ROS release orchestrated by Nox4, Nox2, and mitochondria in VEGF signaling and angiogenesis. Am J Physiol Cell Physiol 312:C749-C764
Das, Archita; Sudhahar, Varadarajan; Chen, Gin-Fu et al. (2016) Endothelial Antioxidant-1: a Key Mediator of Copper-dependent Wound Healing in vivo. Sci Rep 6:33783
Mittal, Manish; Urao, Norifumi; Hecquet, Claudie M et al. (2015) Novel role of reactive oxygen species-activated Trp melastatin channel-2 in mediating angiogenesis and postischemic neovascularization. Arterioscler Thromb Vasc Biol 35:877-87
Chen, Gin-Fu; Sudhahar, Varadarajan; Youn, Seock-Won et al. (2015) Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function. Sci Rep 5:14780
Kohno, Takashi; Urao, Norifumi; Ashino, Takashi et al. (2013) Novel role of copper transport protein antioxidant-1 in neointimal formation after vascular injury. Arterioscler Thromb Vasc Biol 33:805-13
Urao, Norifumi; Ushio-Fukai, Masuko (2013) Redox regulation of stem/progenitor cells and bone marrow niche. Free Radic Biol Med 54:26-39
Sudhahar, Varadarajan; Urao, Norifumi; Oshikawa, Jin et al. (2013) Copper transporter ATP7A protects against endothelial dysfunction in type 1 diabetic mice by regulating extracellular superoxide dismutase. Diabetes 62:3839-50
Kohno, Takashi; Urao, Norifumi; Ashino, Takashi et al. (2013) IQGAP1 links PDGF receptor-? signal to focal adhesions involved in vascular smooth muscle cell migration: role in neointimal formation after vascular injury. Am J Physiol Cell Physiol 305:C591-600
Profirovic, Jasmina; Strekalova, Elena; Urao, Norifumi et al. (2013) A novel regulator of angiogenesis in endothelial cells: 5-hydroxytriptamine 4 receptor. Angiogenesis 16:15-28
Urao, Norifumi; Sudhahar, Varadarajan; Kim, Seok-Jo et al. (2013) Critical role of endothelial hydrogen peroxide in post-ischemic neovascularization. PLoS One 8:e57618

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