Angiopoietins regulate vascular homeostasis via the endothelial Tie receptor tyrosine kinases. Angiopoietin-1 (Ang1) supports endothelial stabilization via Tie2 activation. Angiopoietin-2 (Ang2) functions as a context-dependent Tie2 agonist/antagonist promoting pathological angiogenesis, vascular permeability and inflammation. Elucidating Ang2-dependent mechanisms of vascular destablization is critical for rational design of angiopoietin antagonists that have demonstrated therapeutic efficacy in cancer trials. Here, we report that Ang2, but not Ang1, activates β1-integrin, leading to endothelial destablization. Autocrine Ang2 signalling upon Tie2 silencing, or in Ang2 transgenic mice, promotes β1-integrin-positive elongated matrix adhesions and actin stress fibres, regulating vascular endothelial-cadherin-containing cell–cell junctions. The Tie2-silenced monolayer integrity is rescued by β1-integrin, phosphoinositide-3 kinase or Rho kinase inhibition, and by re-expression of a membrane-bound Tie2 ectodomain. Furthermore, Tie2 silencing increases, whereas Ang2 blocking inhibits transendothelial tumour cell migration in vitro. These results establish Ang2-mediated β1-integrin activation as a promoter of endothelial destablization, explaining the controversial vascular functions of Ang1 and Ang2.
SignificanceCompromised vascular integrity is associated with capillary leakage in sepsis, but effective therapies stabilizing the vasculature are lacking. Here, we show that targeting β1-integrin in vivo with inhibitory antibodies or deletion of a single allele of endothelial β1-integrin inhibits lipopolysaccharide (LPS)-induced vascular leakage in murine endotoxemia. The inflammatory agents IL-1β, thrombin, and LPS induced changes in endothelial cell–extracellular matrix (ECM) adhesion via β1-integrin, angiopoietin-2, and the adapter protein tensin-1, leading to increased endothelial cell contractility and permeability. These results indicate that β1-integrin actively promotes vascular leakage and that targeting β1-integrin signaling could be a novel means of achieving vascular stabilization in pathological vascular leak.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.