Endothelial destabilization by angiopoietin-2 via integrin β1 activation

被引：222

作者：

Hakanpaa, Laura ^{[1
,2
,3
]}

Sipila, Tuomas ^{[1
,2
,3
]}

Leppanen, Veli-Matti ^{[1
,2
]}

Gautam, Prson ^{[1
,2
,3
]}

Nurmi, Harri ^{[1
,2
]}

Jacquemet, Guillaume ^{[4
,5
]}

Eklund, Lauri ^{[6
]}

Ivaska, Johanna ^{[4
,5
]}

Alitalo, Kari ^{[1
,2
]}

Saharinen, Pipsa ^{[1
,2
,3
]}

机构：

[1] Univ Helsinki, Biomedicum Helsinki, Wihuri Res Inst, FI-00014 Helsinki, Finland

[2] Univ Helsinki, Biomedicum Helsinki, Translat Canc Biol Program, Res Programs Unit, FI-00014 Helsinki, Finland

[3] Univ Helsinki, Biomedicum Helsinki, Dept Virol, FI-00014 Helsinki, Finland

[4] Univ Turku, Turku Ctr Biotechnol, FI-20520 Turku, Finland

[5] VTT, FI-20520 Turku, Finland

[6] Univ Oulu, Bioctr Oulu, Oulu Ctr Cell Matrix Res, Fac Biochem & Mol Med, FI-90014 Oulu, Finland

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

芬兰科学院;

关键词：

RECEPTOR TYROSINE KINASE; CELL-JUNCTIONS; SELECTIVE-INHIBITION; TIE2; RECEPTOR; VASCULAR LEAK; TUMOR-GROWTH; VE-CADHERIN; LUNG INJURY; ANGIOGENESIS; ALPHA-V-BETA-3;

D O I：

10.1038/ncomms6962

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 beta 1-integrin, leading to endothelial destablization. Autocrine Ang2 signalling upon Tie2 silencing, or in Ang2 transgenic mice, promotes beta 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 b1-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 b1-integrin activation as a promoter of endothelial destablization, explaining the controversial vascular functions of Ang1 and Ang2.

引用

页数：12

共 55 条

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