Tie1 controls angiopoietin function in vascular remodeling and inflammation
Emilia A. Korhonen, … , Kari Alitalo, Pipsa Saharinen
Emilia A. Korhonen, … , Kari Alitalo, Pipsa Saharinen
Published August 22, 2016
Citation Information: J Clin Invest. 2016;126(9):3495-3510. https://doi.org/10.1172/JCI84923.
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Research Article Angiogenesis Vascular biology Article has an altmetric score of 10

Tie1 controls angiopoietin function in vascular remodeling and inflammation

Abstract

The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a β1 integrin–dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tie1 in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1- and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability.

Authors

Emilia A. Korhonen, Anita Lampinen, Hemant Giri, Andrey Anisimov, Minah Kim, Breanna Allen, Shentong Fang, Gabriela D’Amico, Tuomas J. Sipilä, Marja Lohela, Tomas Strandin, Antti Vaheri, Seppo Ylä-Herttuala, Gou Young Koh, Donald M. McDonald, Kari Alitalo, Pipsa Saharinen

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Figure 9

Effect of LPS on Tie1 levels and ANG1- and autocrine ANG2–induced Tie2 phosphorylation.

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Effect of LPS on Tie1 levels and ANG1- and autocrine ANG2–induced Tie2 p...
(A) Western blot showing phosphorylation of Tie2 in lung lysates from control and Ang2EC mice treated with PBS or LPS. (B) Quantification of phospho-Tie2 relative to total Tie2 from the Western blots in A. (C) Western blot showing phosphorylation of Tie2 in lung lysates of Ad-control– and Ad-CAng1–treated mice with or without LPS treatment. (D) Quantification of phospho-Tie2 relative to total Tie2 from the Western blots in C. (E) Western blotting of Tie1, ANG2, and β-actin in lung lysates from control and Ang2EC mice treated with PBS or LPS. (F) Quantification of Tie1 levels relative to β-actin from the Western blots in E. (G) Western blotting of Tie1, Flag, and Hsc70 in lung lysates from mice treated with Ad-control and Ad-CAng1 with or without LPS treatment. Flag antibody was used to detect CAng1 expression. (H) Quantification of Tie1 levels relative to Hsc70 from the Western blots in E. Error bars indicate SEM. n = 3–7. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA followed by Tukey’s post hoc test. (I) Tie1 (red) and PECAM1 (green) staining of tracheal blood vessels of Ad-control– and Ad-CAng1–treated mice with or without LPS treatment. Representative images (n = 8). Scale bar: 20 μm.