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Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation
Minah Kim, … , Gavin Thurston, Donald M. McDonald
Minah Kim, … , Gavin Thurston, Donald M. McDonald
Published August 22, 2016
Citation Information: J Clin Invest. 2016;126(9):3511-3525. https://doi.org/10.1172/JCI84871.
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Research Article Angiogenesis Vascular biology Article has an altmetric score of 4

Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation

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Abstract

Angiopoietin-2 (ANG2) regulates blood vessel remodeling in many pathological conditions through differential effects on Tie2 signaling. While ANG2 competes with ANG1 to inhibit Tie2, it can paradoxically also promote Tie2 phosphorylation (p-Tie2). A related paradox is that both inactivation and overactivation of Tie2 can result in vascular remodeling. Here, we reconciled these opposing actions of ANG2 by manipulating conditions that govern its actions in the vasculature. ANG2 drove vascular remodeling during Mycoplasma pulmonis infection by acting as a Tie2 antagonist, which led to p-Tie2 suppression, forkhead box O1 (FOXO1) activation, increased ANG2 expression, and vessel leakiness. These changes were exaggerated by anti-Tie2 antibody, inhibition of PI3K signaling, or ANG2 overexpression and were reduced by anti-ANG2 antibody or exogenous ANG1. In contrast, under pathogen-free conditions, ANG2 drove vascular remodeling by acting as an agonist, promoting high p-Tie2, low FOXO1 activation, and no leakage. Tie1 activation was strong under pathogen-free conditions, but infection or TNF-α led to Tie1 inactivation by ectodomain cleavage and promoted the Tie2 antagonist action of ANG2. Together, these data indicate that ANG2 activation of Tie2 supports stable enlargement of normal nonleaky vessels, but reduction of Tie1 in inflammation leads to ANG2 antagonism of Tie2 and initiates a positive feedback loop wherein FOXO1-driven ANG2 expression promotes vascular remodeling and leakage.

Authors

Minah Kim, Breanna Allen, Emilia A. Korhonen, Maximilian Nitschké, Hee Won Yang, Peter Baluk, Pipsa Saharinen, Kari Alitalo, Christopher Daly, Gavin Thurston, Donald M. McDonald

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Figure 6

Reduction in endothelial Tie1 and Tie2 after M.

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Reduction in endothelial Tie1 and Tie2 after M.

pulmonisinfection or TN...
pulmonisinfection or TNF-α. (A) Strong Tie1 and Tie2 staining of tracheal blood vessels under pathogen-free conditions compared with weaker staining after M. pulmonis infection for 7 days. LPS for 16 hours (15 mg/kg i.p.) included as a positive control in A, C, and E (38). (B) Strong colocalization of Tie1 with golgin-97 in enlarged vessels after infection for 7 days. (C) Reduction in Tie1 and Tie2 after infection or LPS (n = 8 per group). *P < 0.05 vs. PF controls, 1-way ANOVA. (D) Greater colocalization of Tie1 and golgin-97 after infection than in pathogen-free controls, assessed by Imaris software (n = 4 per group). *P < 0.05 vs. pathogen-free controls, Student’s t test. (E) Comparison of soluble Tie1 in serum at 1, 3, 5, 7, and 14 days after infection or 16 hours after LPS (15 mg/kg i.p.) normalized to pathogen-free control (n = 5–10 per group). *P < 0.05 vs. pathogen-free controls, 1-way ANOVA. (F) Strong Tie1 and Tie2 in controls compared with weak staining after TNF-α for 6 hours (0.24 mg/kg i.v.) preceded by control human IgG. Less reduction in Tie1 and Tie2 when TNF-α was preceded by anti-ANG2 antibody REGN910 and no reduction when TNF-α was preceded by Tie2-agonist BowANG1. Scale bars: 20 μm. (G and H) Tie1 (G) and Tie2 (H) in vessels of groups shown in F, and after infection for 7 days or LPS for 6 hours (n = 8 per group). *P < 0.05 vs. PF controls; †P < 0.05 vs. corresponding IgG controls, 1-way ANOVA.

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