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

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 8

Inflammation induces Tie1 cleavage and subsequent decrease of Tie2.

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Inflammation induces Tie1 cleavage and subsequent decrease of Tie2. (A) ...
(A) Tie1 expression in tracheal blood vessels of mice treated with LPSfor 16 hours, Tie1 (red, white), and PECAM1 (green) staining. (B) Tie2 expression (green, white) in tracheal blood vessels in the same experiment. Scale bars: 50 μm. (C) Quantification of Tie1 and Tie2 immunostaining in tracheal vessels of the LPS-treated mice, normalized to PBS-treated mice at the indicated time points (h). n = 3. **P < 0.01, ***P < 0.001, 1-way ANOVA followed by Dunnett’s post hoc test. (D) Western blotting of Tie1 extracellular domain (ECD), Tie2, β-actin, phospho-Akt, and Akt in lung lysates from PBS- and LPS-treated control mice. (E) Quantification of Tie1 and Tie2 protein levels from Western blots in D. n = 4, Student’s t test. (F) Representative Western blot of Tie1 in serum from LPS-treated mice at the indicated time points (n = 2–6). (G) sTie1 protein (ng/ml) in serum from control (n = 10) and PUUV disease patients (n = 23). **P < 0.01; ***P < 0.001, Student’s t test. Error bars indicate SEM.