The regulation of vascular endothelial growth factor-induced microvascular permeability requires Rac and reactive oxygen species.
Vascular permeability is a complex process involving the coordinated regulation of multiple signaling pathways in the endothelial cell. It has long been documented that vascular endothelial growth factor (VEGF) greatly enhances microvascular permeability; however, the molecular mechanisms controlling VEGF-induced permeability remain unknown. Treatment of microvascular endothelial cells with VEGF led to an increase in reactive oxygen species (ROS) production. ROS are required for VEGF-induced permeability as treatment with the free radical scavenger, N-acetylcysteine, inhibited this effect. Additionally, treatment with VEGF caused ROS-dependent tyrosine phosphorylation of both vascular-endothelial (VE)-cadherin and beta-catenin. Rac1 was required for the VEGF-induced increase in permeability and adherens junction protein phosphorylation. Knockdown of Rac1 inhibited VEGF-induced ROS production consistent with Rac lying upstream of ROS in this pathway. Collectively, these data suggest that VEGF leads to a Rac-mediated generation of ROS, which, in turn, elevates the tyrosine phosphorylation of VE-cadherin and beta-catenin, ultimately regulating adherens junction integrity.
Monaghan-Benson
Elizabeth
E
Department of Cell and Developmental Biology and Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA. ebenson@med.unc.edu
Burridge
Keith
K
D000111:Acetylcysteine / Q000494:pharmacology; D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000099152:Cadherin 5
D000111:Acetylcysteine; D015703:Antigens, CD; D015820:Cadherins; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D020830:rac1 GTP-Binding Protein; D000099152:Cadherin 5; C107953:RAC1 protein, human; C467484:VEGFA protein, human