Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia.
Vascular endothelial growth factor (VEGF) and Angiopoietin 1 (Ang1) are both potent proangiogenic factors, but, whereas VEGF causes vascular permeability, Ang1 stabilizes blood vessels and protects them from VEGF-induced plasma leakage. The antivascular permeability mechanisms deployed by Ang1 are still undefined. Here, we demonstrate that Ang1 halts the ability of VEGF to induce the phosphorylation-dependent redistribution of the adhesion molecule VE-cadherin, thereby rescuing the endothelial barrier function. Ang1 inhibits the activation of Src by VEGF, the most upstream component of the pathway linking VEGF receptors to VE-cadherin internalization. Indeed, Ang1 promotes the activation of mDia through RhoA, resulting in the association of mDia with Src. This ultimately deprives VEGF receptors of an essential molecule required for promoting the disruption of endothelial cell-cell contacts and paracellular permeability.
Gavard
Julie
J
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-4340, USA.
Patel
Vyomesh
V
Gutkind
J Silvio
JS
D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects / Q000502:physiology*; D042683:Angiopoietin-1 / Q000494:pharmacology*; D015703:Antigens, CD / Q000502:physiology; D015820:Cadherins / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D031541:Fluorescence Resonance Energy Transfer; D000080865:Formins; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D000099152:Cadherin 5
D048868:Adaptor Proteins, Signal Transducing; D042683:Angiopoietin-1; D015703:Antigens, CD; D015820:Cadherins; D002352:Carrier Proteins; D000080865:Formins; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C108962:DIAPH1 protein, human; C491462:DIAPH2 protein, human; C433810:SH3KBP1 protein, human