Angiopoietin-2 sensitizes endothelial cells to TNF-α and has a crucial role in the induction of inflammation
Abstract
The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.
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ANG-2 binds endothelial cell RTK Tie2, activating endothelial migration and proliferation and initiating an NF-κB-dependent inflammatory signaling cascade.
“ANG-2 binds the endothelial cell RTK Tie2, activating endothelial cell migration and proliferation, but also initiating an NF-κB-dependent inflammatory signaling cascade (59).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [59]
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- Authors
- Fiedler, U., Reiss, Y., Scharpfenecker, M., Grunow, V., Koidl, S., Thurston, G., Gale, N. W., Witzenrath, M., Rosseau, S., Suttorp, N., Sobke, A., Herrmann, M., Preissner, K. T., Vajkoczy, P., & Augustin, H. G.
- Affiliations
- Regeneron (United States) (US)
- Humboldt-Universität zu Berlin (DE)
- Universitätsklinikum des Saarlandes (DE)
- Justus-Liebig-Universität Gießen (DE)
- Heidelberg University (DE)
- Corresponding author
- Augustin, Hellmut G
- ORCID
- Venue
- Nature Medicine
- Published
- 2006-02
- Volume
- 12
- Issue
- 2
- Pages
- 235-239
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2164122959
- Cited by
- 933
- References
- 29
- Citations by year
- 2026: 33 · 2025: 34 · 2024: 36 · 2023: 30 · 2022: 43 · 2021: 53 · 2020: 38 · 2019: 35 · 2018: 53 · 2017: 55 · 2016: 47 · 2015: 54 · 2014: 43 · 2013: 54 · 2012: 55
- FWCI
- 20.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- angiopoietin-2, Tie2 receptor, endothelial cells, TNF-α, inflammation, leukocyte adhesion, endothelial adhesion molecules, peritonitis, Staphylococcus aureus, vascular response, autocrine regulation, angiopoietin-1, leukocyte rolling
- MeSH terms
- Animals, Endothelium, Vascular, Humans, Inflammation, Models, Biological, Neovascularization, Pathologic, Tumor Necrosis Factor-alpha, Signal Transduction, Cytokines, Mice, Knockout, Inflammation Mediators, Angiopoietin-1, Angiopoietin-2, Mice
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