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

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 8

Diagram of regulatory loop linking ANG1, ANG2, Tie1, and Tie2 in endothelial cells.

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Diagram of regulatory loop linking ANG1, ANG2, Tie1, and Tie2 in endothe...
(A) Under normal conditions, the agonist action of ANG1 dominates ANG2 in activating Tie2 signaling in a Tie1-dependent manner (38), leading to PI3K/Akt pathway activation. Akt-dependent phosphorylation of FOXO1 suppresses transcriptional function by promoting nuclear exclusion, ubiquitination, and degradation, which increases expression of genes that promote vascular stabilization. (B) After M. pulmonis infection, TNF-α is released, Tie1 is reduced by ectodomain shedding, and Tie2 phosphorylation is suppressed by ANG2 secreted from Weibel-Palade bodies. PI3K/Akt pathway inactivation promotes FOXO1 transcriptional activity and increases expression of ANG2 and other vascular destabilizing genes. The antagonistic action of greater ANG2 dominates the agonist action of ANG1, maintains suppression of Tie2 signaling, and establishes a positive feedback loop, with sustained Akt inactivation, FOXO1 transcriptional activation, and ANG2 production. Vascular destabilization, remodeling, and leakiness are downstream consequences of this ANG2-Tie2 regulatory loop after infection.