Vascular endothelial growth factor (VEGF) regulation of endothelial cell behavior through the Rho family of small GTPases

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  • March 22, 2019
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  • Garrett, Tiana Aisha.
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Vascular endothelial growth factor (VEGF) is an important signaling molecule in endothelial cell behavior and function during embryogenesis and the maintenance of adult tissues. VEGF signaling regulates nascent blood vessel formation (vasculogenesis and angiogenesis) by stimulating endothelial cell migration and decreased barrier integrity (vascular permeability) by modulating endothelial cell-cell junction disassembly. Dysregulated VEGF signaling has been implicated in tumor angiogenesis, ischemic stroke, and a number of other vascular diseases, but the pathways downstream of VEGF signaling remain incompletely defined. VEGF signals through various intracellular effectors to elicit its biological responses. One of these effectors, the Rho family of small GTPases, regulates many cellular processes that involve reorganization of the actin cytoskeleton such as migration and adhesion. Rac1, one member of this family, promotes VEGF-induced endothelial cell migration by stimulating the formation of lamellipodia and membrane ruffles. In addition, Rac1 disrupts vascular barrier integrity by mediating tyrosine phosphorylation of proteins at cell-cell junctions through reactive oxygen species (ROS) redox signaling. Like other GTPases, Rac1 works as a molecular switch that requires the exchange of GDP for GTP to become activated. This activation is stimulated by guanine nucleotide exchange factors (GEFs). VEGF has been shown to activate Rac1 and mediate Rac1-specific biological responses, but the GEFs downstream of VEGF that stimulate Rac1 are unknown. The research described in this dissertation demonstrates that Rac GEF Vav2 couples VEGF signaling to Rac1 in a VEGFR-2- and Src-dependent manner. This signaling pathway is necessary for endothelial cell migration that precedes blood vessel formation. In addition, VEGF stimulates tyrosine phosphorylation of adherens junction proteins [beta]-catenin and VE-cadherin in a ROS-dependent manner, which is essential for vascular permeability.
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  • In Copyright
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  • Burridge, Keith
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Open access
Date uploaded
  • October 19, 2010

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