Reactive Oxygen Species and Endothelial Migration

活性氧和内皮迁移

基本信息

  • 批准号:
    7379914
  • 负责人:
  • 金额:
    $ 37.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-03-15 至 2011-02-28
  • 项目状态:
    已结题

项目摘要

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.
内皮细胞迁移是内皮损伤修复和血管新生的关键。VEGF是 主要通过VEGF 2型受体(VEGFR 2)的EC迁移的有效刺激剂。在静止的EC中, VEGF刺激内皮细胞迁移的最初反应之一是稳定的细胞-细胞间粘附的松动, 接触,其由VE-钙粘蛋白的酪氨酸磷酸化调节。我们发现VEGF刺激 Rac 1依赖性gp 91 phox为基础的NAD(P)H氧化酶和活性氧(ROS)参与 VEGFR 2介导的信号传导与EC迁移相关。潜在的分子机制很差 明白我们最近发现IQGAP 1是一种新的VEGFR 2结合蛋白。它的功能就像一个脚手架 一种通过与细胞骨架和细胞间粘附相互作用来控制细胞运动和形态发生的蛋白质 包括活性Rac 1和E-钙粘蛋白的蛋白质。我们还发现:1)IQGAP 1表达增加, 新生毛细血管内皮细胞在小鼠后肢缺血模型中的血管生成; 2) IQGAP 1增加ECs中基础Rac 1活性、ROS产生和细胞迁移; 3)VEGF促进ECs中Rac 1的表达。 激活的VEGFR 2和Rac 1募集到粘附连接处的IQGAP 1-VE-钙粘蛋白复合物, 这可能促进ROS依赖性的细胞-细胞接触的丧失和随后的EC迁移; 4)伤口 分析显示IQGAP 1与活性VEGFR 2和gp 91 phox在前沿无活性共定位 迁移EC。因此,我们假设IQGAP 1作为VEGFR 2结合支架蛋白发挥作用, ROS依赖信号与VEGF介导的内皮细胞迁移。Aim 1将检查IQGAP 1是否 与VEGFR 2和Rac 1功能性相互作用,将VEGFR 2偶联至与EC相关的ROS依赖性信号传导 迁移Aim 2将检查IQGAP 1是否作为一个支架来募集活化的VEGFR 2和Rac 1 通过与VE-钙粘蛋白结合,从而促进ROS依赖性细胞间粘附的丧失。 联系人,启动EC迁移。Aim 3将研究IQGAP 1在靶向中的支架作用。 VEGFR 2和NAD(P)H氧化酶在定向细胞迁移过程中的前沿。AIM 4将评估 使用小鼠后肢缺血模型的IQGAP 1在体内的功能意义。长期目标是 了解ROS在血管生成背景下调节EC迁移的分子机制 和内皮损伤修复,这将促进新的治疗策略的发展。

项目成果

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Masuko Ushio-Fukai其他文献

Masuko Ushio-Fukai的其他文献

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{{ truncateString('Masuko Ushio-Fukai', 18)}}的其他基金

Mitochondria Dynamics Protein Drp1 in ROS Signaling, Endothelial Metabolism and Angiogenesis
线粒体动力学蛋白 Drp1 在 ROS 信号传导、内皮代谢和血管生成中的作用
  • 批准号:
    10475228
  • 财政年份:
    2021
  • 资助金额:
    $ 37.63万
  • 项目类别:
Mitochondria Dynamics Protein Drp1 in ROS Signaling, Endothelial Metabolism and Angiogenesis
线粒体动力学蛋白 Drp1 在 ROS 信号传导、内皮代谢和血管生成中的作用
  • 批准号:
    10666540
  • 财政年份:
    2021
  • 资助金额:
    $ 37.63万
  • 项目类别:
Mitochondria Dynamics Protein Drp1 in ROS Signaling, Endothelial Metabolism and Angiogenesis
线粒体动力学蛋白 Drp1 在 ROS 信号传导、内皮代谢和血管生成中的作用
  • 批准号:
    10317794
  • 财政年份:
    2021
  • 资助金额:
    $ 37.63万
  • 项目类别:
Protein Disulfide Isomerase as Novel Redox Sensor in VEGF Signaling
蛋白质二硫键异构酶作为 VEGF 信号转导中的新型氧化还原传感器
  • 批准号:
    9479934
  • 财政年份:
    2016
  • 资助金额:
    $ 37.63万
  • 项目类别:
Role of Cysteine Sulfenic Acid Formation in Compartmentalization of VEGF Signalin
半胱氨酸磺酸形成在 VEGF 信号蛋白区室化中的作用
  • 批准号:
    8445715
  • 财政年份:
    2013
  • 资助金额:
    $ 37.63万
  • 项目类别:
Role of Cysteine Sulfenic Acid Formation in Compartmentalization of VEGF Signalin
半胱氨酸磺酸形成在 VEGF 信号蛋白区室化中的作用
  • 批准号:
    8620710
  • 财政年份:
    2013
  • 资助金额:
    $ 37.63万
  • 项目类别:
Reactive Oxygen Species and Endothelial Migration
活性氧和内皮迁移
  • 批准号:
    7844215
  • 财政年份:
    2009
  • 资助金额:
    $ 37.63万
  • 项目类别:
Reactive Oxygen Species and Endothelial Migration
活性氧和内皮迁移
  • 批准号:
    7097600
  • 财政年份:
    2006
  • 资助金额:
    $ 37.63万
  • 项目类别:
Reactive Oxygen Species and Endothelial Migration
活性氧和内皮迁移
  • 批准号:
    7322030
  • 财政年份:
    2006
  • 资助金额:
    $ 37.63万
  • 项目类别:
Reactive Oxygen Species and Endothelial Migration
活性氧和内皮迁移
  • 批准号:
    7579146
  • 财政年份:
    2006
  • 资助金额:
    $ 37.63万
  • 项目类别:

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cGAS-STING 通路靶向具有 CD46 趋向性和 AFP 启动子的复制腺病毒条件性复制限制用于治疗肝细胞癌
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溶瘤腺病毒和免疫代谢佐剂治疗胶质瘤
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  • 财政年份:
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溶瘤腺病毒和免疫代谢佐剂治疗胶质瘤
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探索营养剥夺对 T 细胞和溶瘤腺病毒的影响,以创造用于肿瘤治疗的免疫激活剂
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