Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 9, Pages 3511-3525Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI84871
Keywords
-
Categories
Funding
- National Heart, Lung, and Blood Institute of the NIH [P01 HL024136, R01 HL059157, R01 HL127402]
- Leducq Foundation [11CVD03]
- Angel-Works Foundation
- National Research Foundation of Korea - Ministry of Education [2012-R1A6A3A03040326]
- Academy of Finland (Centre of Excellence Program) [271845]
- European Research Council (ERC) Advanced Grant [ERC-2010-AdG-268804]
- Marie Curie Actions of European Union Seventh Framework Programme (FP7) [317250]
- Sigrid Juselius Foundation
- Finnish Cultural Foundation
- Finnish Cancer Organization
Ask authors/readers for more resources
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 01 (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 FOX01 activation, and no leakage. Tie1 activation was strong under pathogen-free conditions, but infection or TNF-alpha 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available