The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
A role for VEGF as a negative regulator of pericyte function and vessel maturation
Open accessAbstract
Angiogenesis does not only depend on endothelial cell invasion and proliferation: it also requires pericyte coverage of vascular sprouts for vessel stabilization. These processes are coordinated by vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) through their cognate receptors on endothelial cells and vascular smooth muscle cells (VSMCs), respectively. PDGF induces neovascularization by priming VSMCs/pericytes to release pro-angiogenic mediators. Although VEGF directly stimulates endothelial cell proliferation and migration, its role in pericyte biology is less clear. Here we define a role for VEGF as an inhibitor of neovascularization on the basis of its capacity to disrupt VSMC function. Specifically, under conditions of PDGF-mediated angiogenesis, VEGF ablates pericyte coverage of nascent vascular sprouts, leading to vessel destabilization. At the molecular level, VEGF-mediated activation of VEGF-R2 suppresses PDGF-Rβ signalling in VSMCs through the assembly of a previously undescribed receptor complex consisting of PDGF-Rβ and VEGF-R2. Inhibition of VEGF-R2 not only prevents assembly of this receptor complex but also restores angiogenesis in tissues exposed to both VEGF and PDGF. Finally, genetic deletion of tumour cell VEGF disrupts PDGF-Rβ/VEGF-R2 complex formation and increases tumour vessel maturation. These findings underscore the importance of VSMCs/pericytes in neovascularization and reveal a dichotomous role for VEGF and VEGF-R2 signalling as both a promoter of endothelial cell function and a negative regulator of VSMCs and vessel maturation.
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Cites
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Cited by
Pericytes: Developmental, Physiological, and Pathological Perspectives, Problems, and Promises
Armulik, A., Genové, G., & Betsholtz, C. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.07.001 · Cited by 2,653
Macrophages as tools and targets in cancer therapy
Mantovani, A., Allavena, P., Marchesi, F., & Garlanda, C. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00520-5 · Cited by 1,807
Tumor angiogenesis: molecular pathways and therapeutic targets
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Self-citationNormalization of the Vasculature for Treatment of Cancer and Other Diseases
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Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia
Jain, R. K. (2014) · Cancer Cell · doi:10.1016/j.ccell.2014.10.006 · Cited by 1,589
Metadata
- Authors
- Greenberg, J. I., Shields, D. J., Barillas, S. G., Acevedo, L. M., Murphy, E., Huang, J., Scheppke, L., Stockmann, C., Johnson, R. S., Angle, N., & Cheresh, D. A.
- Venue
- Nature
- Published
- 2008-11-09
- Volume
- 456
- Issue
- 7223
- Pages
- 809-813
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2049185799
- Cited by
- 629
- References
- 28
- FWCI
- 18.12
- Type
- journal article
- Language
- en
- Open access
- green
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- Greenberg, J. I., Shields, D. J., Barillas, S. G., Acevedo, L. M., Murphy, E., Huang, J., Scheppke, L., Stockmann, C., Johnson, R. S., Angle, N., & Cheresh, D. A. (2008). A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature. https://doi.org/10.1038/nature07424
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