title: Endothelial destabilization by angiopoietin-2 via integrin β1 activation.
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.
authors: Wihuri Research Institute and Research Programs Unit, Translational Cancer Biology Program and Department of Virology, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors: Laura
authors: L
authors: Hakanpaa
authors: Wihuri Research Institute and Research Programs Unit, Translational Cancer Biology Program and Department of Virology, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors: Tuomas
authors: T
authors: Sipila
authors: Wihuri Research Institute and Research Programs Unit, Translational Cancer Biology, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors: Veli-Matti
authors: VM
authors: Leppanen
authors: Wihuri Research Institute and Research Programs Unit, Translational Cancer Biology Program and Department of Virology, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors: Prson
authors: P
authors: Gautam
authors: Wihuri Research Institute and Research Programs Unit, Translational Cancer Biology, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors: Harri
authors: H
authors: Nurmi
authors: Turku Centre for Biotechnology, University of Turku and VTT, Tykistökatu 6 A, Turku FI-20520, Finland.
authors: Guillaume
authors: G
authors: Jacquemet
authors: Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, PO Box 5400, Biocenter Oulu FI-90014, Finland.
authors: Lauri
authors: L
authors: Eklund
authors: Turku Centre for Biotechnology, University of Turku and VTT, Tykistökatu 6 A, Turku FI-20520, Finland.
authors: Johanna
authors: J
authors: Ivaska
authors: Wihuri Research Institute and Research Programs Unit, Translational Cancer Biology, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors: Kari
authors: K
authors: Alitalo
authors: Wihuri Research Institute and Research Programs Unit, Translational Cancer Biology Program and Department of Virology, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors: Pipsa
authors: P
authors: Saharinen
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D019012:Integrin beta1; D042787:Receptor, TIE-2
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