Angiopoietin-2 Is Critical for Cytokine-Induced Vascular Leakage
Open accessAbstract
Genetic experiments (loss-of-function and gain-of-function) have established the role of Angiopoietin/Tie ligand/receptor tyrosine kinase system as a regulator of vessel maturation and quiescence. Angiopoietin-2 (Ang-2) acts on Tie2-expressing resting endothelial cells as an antagonistic ligand to negatively interfere with the vessel stabilizing effects of constitutive Ang-1/Tie-2 signaling. Ang-2 thereby controls the vascular response to inflammation-inducing as well as angiogenesis-inducing cytokines. This study was aimed at assessing the role of Ang-2 as an autocrine (i.e. endothelial-derived) regulator of rapid vascular responses (within minutes) caused by permeability-inducing agents. Employing two independent in vivo assays to quantitatively assess vascular leakage (tracheal microsphere assay, 1-5 min and Miles assay, 20 min), the immediate vascular response to histamine, bradykinin and VEGF was analyzed in Ang-2-deficient (Ang-2(-/-)) mice. In comparison to the wild type control mice, the Ang2(-/-) mice demonstrated a significantly attenuated response. The Ang-2(-/-) phenotype was rescued by systemic administration (paracrine) of an adenovirus encoding Ang-2. Furthermore, cytokine-induced intracellular calcium influx was impaired in Ang-2(-/-) endothelioma cells, consistent with reduced phospholipase activation in vivo. Additionally, recombinant human Ang-2 (rhAng-2) alone was unable to induce vascular leakage. In summary, we report here in a definite genetic setting that Ang-2 is critical for multiple vascular permeability-inducing cytokines.
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ANG2, which is up-regulated in diseases associated with inflammation and vascular leakage, synergizes with multiple inflammatory agents, promoting endothelial permeability.
“Furthermore, the EC-derived growth factor angiopoietin-2 (ANG2, ANGPT2), which is up-regulated in diseases associated with inflammation and vascular leakage, synergizes with multiple inflammatory agents, promoting endothelial permeability (6, 7).”
From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [7]
The Discussion reports that Ang-2 sensitizes vessels to leakage induced by histamine, bradykinin and VEGF, supporting the permeability claim. The Introduction identifies Ang-2 as endothelial-derived, but the passages found do not establish that it is up-regulated in diseases associated with inflammation and vascular leakage. (LLM, conf=0.84)
Experimental — accuracy not yet measuredANGPT2 is a context-dependent regulator of vascular stability and synergizes with inflammatory agents to induce vascular leak, via mechanisms involving inhibition of ANGPT1-TIE2 signaling and the thrombin-induced calcium response.
“ANGPT2 is a context-dependent regulator of vascular stability and synergizes with inflammatory agents to induce vascular leak, via mechanisms involving inhibition of ANGPT1-TIE2 signaling and the thrombin-induced calcium response (7, 17).”
From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [7]
The Introduction describes Ang-2 as a context-dependent Tie-2 regulator, and the Discussion reports that loss of Ang-2 attenuates leakage induced by histamine, bradykinin and VEGF while supporting its antagonism of Ang-1/Tie-2 signaling. The Results link Ang-2 to calcium responses to histamine and VEGF, but our copy does not report a thrombin-induced calcium response. (LLM, conf=0.88)
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Self-citation
- Authors
- Benest, A. V., Kruse, K., Savant, S., Thomas, M., Laib, A. M., Loos, E. K., Fiedler, U., & Augustin, H. G.
- Affiliations
- German Cancer Research Center (DE)
- Corresponding author
- Augustin, Hellmut G.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-08-05
- Volume
- 8
- Issue
- 8
- Pages
- e70459
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3734283
- OpenAlex
- W2008455196
- Cited by
- 178
- References
- 36
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 23 · 2023: 18 · 2022: 10 · 2021: 15 · 2020: 20 · 2019: 10 · 2018: 13 · 2017: 10 · 2016: 17 · 2015: 11 · 2014: 6
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Regeneron Pharmaceuticals
- Deutsche Forschungsgemeinschaft (Project A3, SFB‐TR23)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- angiopoietin-2, vascular leakage, vascular permeability, histamine, bradykinin, vascular endothelial growth factor, endothelial cells, intracellular calcium influx, phospholipase activation
- MeSH terms
- Animals, Bradykinin, Capillary Permeability, Cells, Cultured, Female, Lung, Recombinant Fusion Proteins, Blotting, Western, Cytokines, Mice, Knockout, Vascular Endothelial Growth Factor A, Angiopoietin-2, Mice, Human Umbilical Vein Endothelial Cells
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