Hakanpaa Laura, Sipila Tuomas, Leppanen Veli-Matti, Gautam Prson, Nurmi Harri, Jacquemet Guillaume, Eklund Lauri, Ivaska Johanna, Alitalo Kari, Saharinen Pipsa
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.
Wihuri Research Institute and Research Programs Unit, Translational Cancer Biology, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
Nat Commun. 2015 Jan 30;6:5962. doi: 10.1038/ncomms6962.
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.
血管生成素通过内皮细胞Tie受体酪氨酸激酶调节血管稳态。血管生成素-1（Ang1）通过激活Tie2来支持内皮细胞的稳定。血管生成素-2（Ang2）作为一种依赖于环境的Tie2激动剂/拮抗剂，促进病理性血管生成、血管通透性和炎症。阐明Ang2依赖的血管不稳定机制对于合理设计血管生成素拮抗剂至关重要，这些拮抗剂在癌症试验中已显示出治疗效果。在此，我们报告Ang2而非Ang1激活β1整合素，导致内皮细胞不稳定。在Tie2沉默时或在Ang2转基因小鼠中，自分泌的Ang2信号促进β1整合素阳性的细长基质黏附及肌动蛋白应力纤维，调节含血管内皮钙黏蛋白的细胞间连接。通过抑制β1整合素、磷酸肌醇-3激酶或Rho激酶，以及重新表达膜结合的Tie2胞外域，可挽救Tie2沉默的单层细胞完整性。此外，Tie2沉默会增加体外跨内皮肿瘤细胞迁移，而阻断Ang2则会抑制这种迁移。这些结果表明，Ang2介导的β1整合素激活是内皮细胞不稳定的促进因素，解释了Ang1和Ang2在血管功能方面存在争议的原因。
