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

84 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

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Angiopoietin-2
destabilization
Integrins
Chemical activation
activation
homeostasis
angiogenesis
tyrosine
Angiopoietin-1
cells
integrity
mice
permeability
adhesion
tumors
stabilization
cancer
Angiopoietins
membranes
Blood Vessels

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Hakanpää, L., Sipilä, T., Leppänen, V-M., Gautam, P., Nurmi, H., Jacquemet, G., ... Saharinen, P. (2015). Endothelial destabilization by angiopoietin-2 via integrin ß1 activation. Nature Communications, 6, [5962]. https://doi.org/10.1038/ncomms6962
Hakanpää, Laura ; Sipilä, Tuomas ; Leppänen, Veli-Matti ; Gautam, Prson ; Nurmi, H. ; Jacquemet, Guillaume ; Eklund, Lauri ; Ivaska, Johanna ; Alitalo, Kari ; Saharinen, Pipsa. / Endothelial destabilization by angiopoietin-2 via integrin ß1 activation. In: Nature Communications. 2015 ; Vol. 6.
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title = "Endothelial destabilization by angiopoietin-2 via integrin {\ss}1 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 {\ss}1-integrin, leading to endothelial destablization. Autocrine Ang2 signalling upon Tie2 silencing, or in Ang2 transgenic mice, promotes {\ss}1-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 {\ss}1-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 {\ss}1-integrin activation as a promoter of endothelial destablization, explaining the controversial vascular functions of Ang1 and Ang2.",
author = "Laura Hakanp{\"a}{\"a} and Tuomas Sipil{\"a} and Veli-Matti Lepp{\"a}nen and Prson Gautam and H. Nurmi and Guillaume Jacquemet and Lauri Eklund and Johanna Ivaska and Kari Alitalo and Pipsa Saharinen",
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Hakanpää, L, Sipilä, T, Leppänen, V-M, Gautam, P, Nurmi, H, Jacquemet, G, Eklund, L, Ivaska, J, Alitalo, K & Saharinen, P 2015, 'Endothelial destabilization by angiopoietin-2 via integrin ß1 activation', Nature Communications, vol. 6, 5962. https://doi.org/10.1038/ncomms6962

Endothelial destabilization by angiopoietin-2 via integrin ß1 activation. / Hakanpää, Laura; Sipilä, Tuomas; Leppänen, Veli-Matti; Gautam, Prson; Nurmi, H.; Jacquemet, Guillaume; Eklund, Lauri; Ivaska, Johanna; Alitalo, Kari; Saharinen, Pipsa (Corresponding Author).

In: Nature Communications, Vol. 6, 5962, 2015.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Endothelial destabilization by angiopoietin-2 via integrin ß1 activation

AU - Hakanpää, Laura

AU - Sipilä, Tuomas

AU - Leppänen, Veli-Matti

AU - Gautam, Prson

AU - Nurmi, H.

AU - Jacquemet, Guillaume

AU - Eklund, Lauri

AU - Ivaska, Johanna

AU - Alitalo, Kari

AU - Saharinen, Pipsa

PY - 2015

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N2 - 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.

AB - 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.

U2 - 10.1038/ncomms6962

DO - 10.1038/ncomms6962

M3 - Article

VL - 6

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 5962

ER -

Hakanpää L, Sipilä T, Leppänen V-M, Gautam P, Nurmi H, Jacquemet G et al. Endothelial destabilization by angiopoietin-2 via integrin ß1 activation. Nature Communications. 2015;6. 5962. https://doi.org/10.1038/ncomms6962