Reactive Oxygen Species and Endothelial Migration

Project: Research project

Project Details

Description

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.
StatusNot started

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