The Regulation of Vascular Endothelial Growth Factor-induced Microvascular Permeability Requires Rac and Reactive Oxygen Species

• Published in: The Journal of biological chemistry Vol. 284; no. 38; pp. 25602 - 25611
• Main Authors: Monaghan-Benson, Elizabeth, Burridge, Keith
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.09.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Acetylcysteine - pharmacology; Adherens Junctions - genetics; Adherens Junctions - metabolism; Antigens, CD - metabolism; beta Catenin - metabolism; Cadherins - metabolism; Capillary Permeability - drug effects; Capillary Permeability - physiology; Cells, Cultured; Endothelial Cells - metabolism; Endothelium, Vascular - metabolism; Free Radical Scavengers - pharmacology; Humans; Mechanisms of Signal Transduction; Phosphorylation - drug effects; Phosphorylation - physiology; rac1 GTP-Binding Protein - metabolism; Reactive Oxygen Species - metabolism; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.009894

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 β-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 β-catenin, ultimately regulating adherens junction integrity.