Endothelial destabilization by angiopoietin-2 via integrin β1 activation

Laura Hakanpaa, Tuomas Sipila, Veli-Matti Leppanen, Prson Gautam, Harri Nurmi, Guillaume Jacquemet, Lauri Eklund, Johanna Ivaska, Kari Alitalo and Pipsa Saharinen ()
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Laura Hakanpaa: Wihuri Research Institute and Research Programs Unit, University of Helsinki, Biomedicum Helsinki
Tuomas Sipila: Wihuri Research Institute and Research Programs Unit, University of Helsinki, Biomedicum Helsinki
Veli-Matti Leppanen: Wihuri Research Institute and Research Programs Unit, Translational Cancer Biology, University of Helsinki, Biomedicum Helsinki
Prson Gautam: Wihuri Research Institute and Research Programs Unit, University of Helsinki, Biomedicum Helsinki
Harri Nurmi: Wihuri Research Institute and Research Programs Unit, Translational Cancer Biology, University of Helsinki, Biomedicum Helsinki
Guillaume Jacquemet: Turku Centre for Biotechnology, University of Turku and VTT, Tykistökatu 6 A, Turku FI-20520, Finland
Lauri Eklund: Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu
Johanna Ivaska: Turku Centre for Biotechnology, University of Turku and VTT, Tykistökatu 6 A, Turku FI-20520, Finland
Kari Alitalo: Wihuri Research Institute and Research Programs Unit, Translational Cancer Biology, University of Helsinki, Biomedicum Helsinki
Pipsa Saharinen: Wihuri Research Institute and Research Programs Unit, University of Helsinki, Biomedicum Helsinki

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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 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.

Date: 2015
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DOI: 10.1038/ncomms6962

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