Angiogenesis does not only depend on endothelial cell invasion and proliferation: it also requires pericyte coverage of vascular sprouts for vessel stabilization1,2. 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), respectively3,4. PDGF induces neovascularization by priming VSMCs/pericytes to release pro-angiogenic mediators5,6,7. 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-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 neovascularization8,9 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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We thank D. Stupack and D. Schlaepfer for advice and review of the manuscript. We also thank A. Tomar for assistance with the PLA imaging; C. Heldin for the PDGF-Rβ complementary DNA; and J. Desgrosellier for processing pancreatic tumour samples. This work was supported by National Institutes of Health grants R37-CA50286 (D.A.C.) and CA082515 (R.S.J.), and by a University of California Academic Senate Grant (N.A.). C.S. was funded by the Deutsche Forschungsgemeinschaft (DFG STO 787/1-1), and L.M.A. received an Institutional Research and Academic Career Development Award postdoctoral fellowship (National Institutes of Health grant GM 68524).
Author Contributions J.I.G. generated mutant receptors, performed biochemical and cell imaging analyses, and prepared the manuscript. D.J.S. and E.M. assisted with experiments and manuscript preparation. S.G.B. performed angiogenesis assays. L.M.A. assisted with adenovirus production, cell isolation and tumour staining. J.H. and L.S. performed RNA analysis and assisted with biochemical analyses. C.S. and R.S.J. generated, implanted and harvested fibrosarcomas. D.A.C. and N.A. supervised and directed the project.
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Greenberg, J., Shields, D., Barillas, S. et al. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456, 809–813 (2008) doi:10.1038/nature07424
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