Opposing effect of angiopoietin‐1 on VEGF‐mediated disruption of endothelial cell–cell interactions requires activation of PKCβ

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Abstract
Angiopoietin‐1 (Ang1) and vascular endothelial growth factor (VEGF) cooperate in migration and survival of endothelial cells by activation of phosphatidylinositol‐3 (PI‐3) kinase and mitogen activating protein (MAP) kinase pathways. However, Ang1 opposes the effect of VEGF on vascular permeability. We found that Ang1 also blocks VEGF‐mediated diffusion of fluoresin isothiocyanate (FITC)‐labeled albumin across an endothelial cell monolayer. VEGF‐mediated vascular permeability has been attributed, in part, to activation of phospholipase A2 and subsequent formation of platelet activating factor. However, Ang1 had no effect on VEGF‐induced activation of phospholipase A2 or the release of arachidonic acid. VEGF‐mediated permeability was associated with disruption of endothelial cell junctional complexes, dissociation of β‐catenin from VE‐cadherin, and accumulation of β‐catenin in the cytosol. In contrast, Ang1 enhanced the interaction of β‐catenin with VE‐cadherin and impaired VEGF‐mediated dissociation of this complex. Ang1 also blocked VEGF‐induced translocation of protein kinase C (PKC) and β2 to the membrane, but had no effect on activation of PKCα. In addition, staurosporine and a PKCβ inhibitor, LY379196, blocked VEGF‐mediated dissociation of β‐catenin from VE‐cadherin, diffusion of albumin across the endothelial cell monolayer, and translocation of PKCβ isoforms. These data indicate that VEGF‐mediated disruption of endothelial cell–cell interactions requires activation of PKCβ isoforms and that this pathway is blocked by Ang1. J. Cell. Physiol. 198: 53–61, 2004.