Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling
Open accessAbstract
Angiopoietin-2 (ANG-2) is a key regulator of angiogenesis that exerts context-dependent effects on ECs. ANG-2 binds the endothelial-specific receptor tyrosine kinase 2 (TIE2) and acts as a negative regulator of ANG-1/TIE2 signaling during angiogenesis, thereby controlling the responsiveness of ECs to exogenous cytokines. Recent data from tumors indicate that under certain conditions ANG-2 can also promote angiogenesis. However, the molecular mechanisms of dual ANG-2 functions are poorly understood. Here, we identify a model for the opposing roles of ANG-2 in angiogenesis. We found that angiogenesis-activated endothelium harbored a subpopulation of TIE2-negative ECs (TIE2lo). TIE2 expression was downregulated in angiogenic ECs, which abundantly expressed several integrins. ANG-2 bound to these integrins in TIE2lo ECs, subsequently inducing, in a TIE2-independent manner, phosphorylation of the integrin adaptor protein FAK, resulting in RAC1 activation, migration, and sprouting angiogenesis. Correspondingly, in vivo ANG-2 blockade interfered with integrin signaling and inhibited FAK phosphorylation and sprouting angiogenesis of TIE2lo ECs. These data establish a contextual model whereby differential TIE2 and integrin expression, binding, and activation control the role of ANG-2 in angiogenesis. The results of this study have immediate translational implications for the therapeutic exploitation of angiopoietin signaling.
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ANGPTs can signal via integrins to modulate vascular responses beyond the primary signaling mode through TIE2.
“Recent studies have demonstrated that beyond the primary signaling mode through TIE2, ANGPTs can also signal via integrins to modulate vascular responses (13, 21–25).”
From Inactive β1-integrin acts as a junctional scaffold for angiopoietin/TIE2/FOXO1 signaling (2026) · cites this paper as [21]
Integrins have been identified as alternative receptors for the angiopoietins in certain Tie2-negative non-endothelial cells and in endothelial tip cells of angiogenic vessel sprouts, which express low levels of Tie2.
“Integrins, which regulate endothelial cell–cell and cell–matrix interactions, have been identified as alternative receptors for the angiopoietins in certain Tie2-negative non-endothelial cells22232425, and in the endothelial tip cells of angiogenic vessel sprouts, which express low levels of Tie2 (refs 26, 27).”
From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [27]
Our results differentiating between Ang1- and Ang2-mediated β1-integrin activation in the absence of Tie2 are in line with Ang2-integrin signalling in the endothelial tip cells, which express high Ang2 but low Tie2 levels.
“Our results differentiating between Ang1- and Ang2-mediated β1-integrin activation in the absence of Tie2 are in line with Ang2-integrin signalling in the endothelial tip cells, which express high Ang2 but low Tie2 levels27.”
From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [27]
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THE ANGIOPOIETIN/TIE PATHWAY IN RETINAL VASCULAR DISEASES
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- Authors
- Felcht, M., Luck, R., Schering, A., Seidel, P., Srivastava, K., Hu, J., Bartol, A., Kienast, Y., Vettel, C., Loos, E. K., Kutschera, S., Bartels, S., Appak, S., Besemfelder, E., Terhardt, D., Chavakis, E., Wieland, T., Klein, C., Thomas, M., Uemura, A., Goerdt, S., & Augustin, H. G.
- Affiliations
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Goethe University Frankfurt (DE)
- Corresponding author
- Augustin, Hellmut G.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2012-06-01
- Volume
- 122
- Issue
- 6
- Pages
- 1991-2005
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3366398
- OpenAlex
- W2157985193
- Cited by
- 479
- References
- 50
- Citations by year
- 2026: 20 · 2025: 33 · 2024: 28 · 2023: 44 · 2022: 29 · 2021: 21 · 2020: 31 · 2019: 36 · 2018: 37 · 2017: 40 · 2016: 40 · 2015: 37 · 2014: 41 · 2013: 30 · 2012: 12
- FWCI
- 15.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsches Krebsforschungszentrum
- Deutsche Forschungsgemeinschaft (Project B6, SFB873, SFB‐TR23)
- Aventis Foundation
- Japan Society for the Promotion of Science (22689046)
- 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
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- angiopoietin-2, angiogenesis, Tie2, integrin signaling, FAK phosphorylation, Rac1 activation, sprouting angiogenesis, endothelial cells, tumor angiogenesis
- MeSH terms
- Animals, Female, Humans, Male, Melanoma, Neoplasm Proteins, Neovascularization, Pathologic, Neuropeptides, Phosphorylation, Signal Transduction, Down-Regulation, Integrins, rac GTP-Binding Proteins, Receptor Protein-Tyrosine Kinases, rac1 GTP-Binding Protein, Angiopoietin-2, Endothelial Cells, Receptor, TIE-2, Mice, Focal Adhesion Kinase 1
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