Endothelial destabilization by angiopoietin-2 via integrin ß1 activation

Laura Hakanpää, Tuomas Sipilä, Veli-Matti Leppänen, Prson Gautam, H. Nurmi, Guillaume Jacquemet, Lauri Eklund, Johanna Ivaska, Kari Alitalo, Pipsa Saharinen (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

105 Citations (Scopus)

Abstract

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 ß1-integrin, leading to endothelial destablization. Autocrine Ang2 signalling upon Tie2 silencing, or in Ang2 transgenic mice, promotes ß1-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 ß1-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 ß1-integrin activation as a promoter of endothelial destablization, explaining the controversial vascular functions of Ang1 and Ang2.
Original languageEnglish
Article number5962
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 2015
MoE publication typeA1 Journal article-refereed

Fingerprint Dive into the research topics of 'Endothelial destabilization by angiopoietin-2 via integrin ß1 activation'. Together they form a unique fingerprint.

Cite this