A role for VEGF as a negative regulator of pericyte function and vessel maturation

Abstract

VEGF (vascular endothelial growth factor) is an important angiogenic factor that has been implicated in tumorigenesis. Two papers now show that the function of VEGF is far more complex, as VEFG can negatively regulate angiogenesis and limit tumorigenesis. In one study, Greenberg et al. found that VEGF can inhibit angiogenesis, by impeding the function of the PDGF (platelet-derived growth factor) receptor on pericytes, leading to a loss of pericyte coverage of blood vessels. This involves the formation of heterodimers between the receptors for VEGF and PDGF. In another paper, Stockmann et al. deleted VEGF production in myeloid cells, but not other cell types. Unexpectedly, they found more rapid tumour development in these mice, at the same time as attenuated tumour vascularization and the formation of morphologically and functionally normalized blood vessels. In contrast, tumours lacking VEGF altogether grew more slowly. VEGF is an important angiogenic factor that has been implicated in tumourigenesis. Two papers now show that the function of VEGF is far more complex, as VEGF can negatively regulate angiogenesis and limit tumourigenesis. This study found that VEGF can inhibit angiogenesis by impeding the function of the PDGF receptor on pericytes, leading to a loss of pericyte coverage of blood vessels. This involves the formation of heterodimers between the receptors for VEGF and PDGF. 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.