Journal
NATURE
Volume 456, Issue 7223, Pages 809-U101Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature07424
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Funding
- National Institutes of Health [R37-CA50286, CA082515, GM 68524]
- University of California Academic Senate Grant
- Deutsche Forschungsgemeinschaft [DFG STO 787/1-1]
- Institutional Research and Academic Career Development Award
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Angiogenesis does not only depend on endothelial cell invasion and proliferation: it alsorequires pericyte coverage of vascular sprouts for vessel stabilization(1,2). 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(3,4). PDGF induces neovascularization by priming VSMCs/pericytes to release proangiogenic mediators(5-7). 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- R beta signalling in VSMCs through the assembly of a previously undescribed receptor complex consisting of PDGF- Rb 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-R beta/VEGF-R2 complex formation and increases tumour vessel maturation. These findings underscore the importance of VSMCs/ pericytes in neovascularization(8,9) and reveal a dichotomous role forVEGF 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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