Opposing effect of angiopoietin-1 on VEGF-mediated disruption of endothelial cell-cell interactions requires activation of PKC beta

J Cell Physiol. 2004 Jan;198(1):53-61. doi: 10.1002/jcp.10386.

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 A(2) and subsequent formation of platelet activating factor. However, Ang1 had no effect on VEGF-induced activation of phospholipase A(2) or the release of arachidonic acid. VEGF-mediated permeability was associated with disruption of endothelial cell junctional complexes, dissociation of beta-catenin from VE-cadherin, and accumulation of beta-catenin in the cytosol. In contrast, Ang1 enhanced the interaction of beta-catenin with VE-cadherin and impaired VEGF-mediated dissociation of this complex. Ang1 also blocked VEGF-induced translocation of protein kinase C (PKC) and beta2 to the membrane, but had no effect on activation of PKC alpha. In addition, staurosporine and a PKC beta inhibitor, LY379196, blocked VEGF-mediated dissociation of beta-catenin from VE-cadherin, diffusion of albumin across the endothelial cell monolayer, and translocation of PKC beta isoforms. These data indicate that VEGF-mediated disruption of endothelial cell-cell interactions requires activation of PKC beta isoforms and that this pathway is blocked by Ang1.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Albumins / metabolism
  • Angiopoietin-1 / metabolism*
  • Animals
  • Antigens, CD
  • Cadherins / metabolism
  • Capillary Permeability*
  • Cell Communication / physiology*
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Enzyme Activation
  • Humans
  • Isoenzymes / metabolism
  • Platelet Activating Factor / metabolism
  • Protein Kinase C / metabolism*
  • Protein Kinase C beta
  • Protein Kinase C-alpha
  • Trans-Activators / metabolism
  • Vascular Endothelial Growth Factor A / metabolism*
  • beta Catenin

Substances

  • Albumins
  • Angiopoietin-1
  • Antigens, CD
  • CTNNB1 protein, human
  • Cadherins
  • Cytoskeletal Proteins
  • Isoenzymes
  • Platelet Activating Factor
  • Trans-Activators
  • Vascular Endothelial Growth Factor A
  • beta Catenin
  • cadherin 5
  • PRKCA protein, human
  • Protein Kinase C
  • Protein Kinase C beta
  • Protein Kinase C-alpha