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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

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 1

ANG2 expression in endothelial cells at sites of vascular remodeling.

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ANG2 expression in endothelial cells at sites of vascular remodeling.
(A...
(A and B) Weak or absent ANG2 immunofluorescence in normal tracheal blood vessels of pathogen-free wild-type mouse (A) and Ang2-EGFP mouse (B) compared with strong ANG2 staining in remodeled vessels in both types of mice after M. pulmonis infection for 7 days. (C) Comparison of no ANG2 staining in vessels of control mouse with strong staining in enlarged vessels after ANG2 overexpression in endothelial cells of Tie1-ANG2 mouse off doxycycline from birth to 8 weeks. (D) Comparison of no ANG2 staining in vessels of control mouse with strong staining in bulbous vascular expansions (arrowheads) after VEGF-A overexpression in CC10–VEGF-A mouse on doxycycline for 7 days. Boxed region enlarged on the right. Scale bars: 10 μm. (E and F) Comparison of ANG2 immunofluorescence of tracheal blood vessels in C57BL/6 mice (E) and EGFP staining in Ang2-EGFP mice (F) under pathogen-free conditions and after infection for 7 days (n = 12 per group). *P < 0.05 vs. pathogen-free, Student’s t test. (G) Correlation (P = 0.0001) between amount of ANG2 staining and size of 34 tracheal vessels in 12 pathogen-free Tie1-ANG2 mice off doxycycline from birth to 8 weeks of age.
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