1. Department of Surgery, School of Medicine,
2. Department of Pathology and Moore's UCSD Cancer Center,
3. Section of Molecular Biology, Division of Biology, University of California, San Diego, California 92093, USA

Correspondence to: David A. Cheresh² Correspondence and requests for materials should be addressed to D.A.C. (Email: dcheresh@ucsd.edu).

Abstract

Angiogenesis does not only depend on endothelial cell invasion and proliferation: it also requires 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 pro-angiogenic mediators^{5, 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-R signalling in VSMCs through the assembly of a previously undescribed receptor complex consisting of PDGF-R 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/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 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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