The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Vascular-specific growth factors and blood vessel formation
Yancopoulos, G. D., Davis, S., Gale, N. W., Rudge, J. S., Wiegand, S. J., & Holash, J. (2000) · Nature · doi:10.1038/35025215 · Cited by 3,699
A gene expression atlas of the central nervous system based on bacterial artificial chromosomes
Gong, S., Zheng, C., Doughty, M. L., Losos, K., Didkovsky, N., Schambra, U. B., Nowak, N. J., Joyner, A., Leblanc, G., Hatten, M. E., et al. (2003) · Nature · doi:10.1038/nature02033 · Cited by 2,108
Fiedler, U., Reiss, Y., Scharpfenecker, M., Grunow, V., Koidl, S., Thurston, G., Gale, N. W., Witzenrath, M., Rosseau, S., Suttorp, N., et al. (2006) · Nature Medicine · doi:10.1038/nm1351 · Cited by 933
Self-citationIncreased Vascularization in Mice Overexpressing Angiopoietin-1
Suri, C., McClain, J., Thurston, G., McDonald, D. M., Zhou, H., Oldmixon, E. H., Sato, T. N., & Yancopoulos, G. D. (1998) · Science · doi:10.1126/science.282.5388.468 · Cited by 818
Self-citationKim, I., Kim, H. G., So, J.-N., Kim, J. H., Kwak, H. J., & Koh, G. Y. (2000) · Circulation Research · doi:10.1161/01.res.86.1.24 · Cited by 649
Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans
Parikh, S. M., Mammoto, T., Schultz, A., Yuan, H.-T., Christiani, D., Karumanchi, S. A., & Sukhatme, V. P. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030046 · Cited by 527
Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling
Felcht, M., Luck, R., Schering, A., Seidel, P., Srivastava, K., Hu, J., Bartol, A., Kienast, Y., Vettel, C., Loos, E. K., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58832 · Cited by 479
Endothelial destabilization by angiopoietin-2 via integrin β1 activation
Hakanpaa, L., Sipila, T., Leppanen, V.-M., Gautam, P., Nurmi, H., Jacquemet, G., Eklund, L., Ivaska, J., Alitalo, K., & Saharinen, P. (2015) · Nature Communications · doi:10.1038/ncomms6962 · Cited by 287
Self-citationTie1 controls angiopoietin function in vascular remodeling and inflammation
Korhonen, E. A., Lampinen, A., Giri, H., Anisimov, A., Kim, M., Allen, B., Fang, S., D’Amico, G., Sipilä, T. J., Lohela, M., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84923 · Cited by 283
Self-citationAngiopoietin-2 Is Critical for Cytokine-Induced Vascular Leakage
Benest, A. V., Kruse, K., Savant, S., Thomas, M., Laib, A. M., Loos, E. K., Fiedler, U., & Augustin, H. G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070459 · Cited by 178
Cited by
Permeability of the Endothelial Barrier: Identifying and Reconciling Controversies
Claesson-Welsh, L., Dejana, E., & McDonald, D. M. (2021) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.11.006 · Cited by 631
Self-citationTherapeutic targeting of the angiopoietin–TIE pathway
Saharinen, P., Eklund, L., & Alitalo, K. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.278 · Cited by 620
Self-citationRole of Angiopoietin-2 in Vascular Physiology and Pathophysiology
Akwii, R. G., Sajib, M. S., Zahra, F. T., & Mikelis, C. M. (2019) · Cells · doi:10.3390/cells8050471 · Cited by 543
Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease
Hammoutene, A., & Rautou, P.-E. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.02.012 · Cited by 364
Retinal vasculature development in health and disease
Selvam, S., Kumar, T., & Fruttiger, M. (2018) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.11.001 · Cited by 353
Metadata
- Authors
- Kim, M., Allen, B., Korhonen, E. A., Nitschké, M., Yang, H. W., Baluk, P., Saharinen, P., Alitalo, K., Daly, C., Thurston, G., & McDonald, D. M.
- Venue
- Journal of Clinical Investigation
- Published
- 2016-08-22
- Volume
- 126
- Issue
- 9
- Pages
- 3511-3525
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- OpenAlex
- W2515730584
- Cited by
- 243
- References
- 10
- FWCI
- 8.13
- Type
- journal article
- Language
- en
- Open access
- bronze
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
How to cite
Cite CoChat for the checks on this page, and the paper for its own findings.
- This page
- CoChat. (2026). Citation check: Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation. https://app.cochat.ai/papers/10.1172/jci84871
- The paper
- Kim, M., Allen, B., Korhonen, E. A., Nitschké, M., Yang, H. W., Baluk, P., Saharinen, P., Alitalo, K., Daly, C., Thurston, G., & McDonald, D. M. (2016). Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation. Journal of Clinical Investigation. https://doi.org/10.1172/jci84871
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
