Angiopoietins-1 and -2 are both capable of mediating endothelial PAF synthesis: intracellular signalling pathways

Vascular endothelial growth factor (VEGF) is the only angiogenic growth factor capable of inducing an inflammatory response and we have recently demonstrated that its inflammatory effect is mediated by the endothelial synthesis of platelet-activating factor (PAF). Recently discovered, Ang1 and Ang2, upon binding to Tie2 receptor, modulate vascular permeability and integrity, contributing to angiogenesis. Ang1 was initially identified as a Tie2 agonist whereas Ang2 can behave as a context-dependent Tie2 agonist or antagonist. We sought to determine if Ang1 and/or Ang2 could modulate PAF synthesis in bovine aortic endothelial cells (BAEC) and if so, through which intracellular signalling pathways. Herein, we report that Ang1 and Ang2 (1 nM) are both capable of mediating a rapid Tie2 phosphorylation and a rapid, progressive and sustained endothelial PAF synthesis maximal within 4 h (1695% and 851% increase, respectively). Angiopoietin-mediated endothelial PAF synthesis requires the activation of the p38 and p42/44 MAPKs, PI3K intracellular signalling pathways, and a secreted phospholipase A(2) (sPLA(2)-V). Furthermore, angiopoietin-mediated PAF synthesis is partly driven by a relocalization of endogenous VEGF to the cell surface membrane. Our results demonstrate that the angiopoietins constitute another class of angiogenic factors capable of mediating PAF synthesis which may contribute to proinflammatory activities.