A Role for VEGF as a Negative Regulator of Pericyte Function and Vessel Maturation

By J. Greenberg, D. Shields, S. Barillas, Lisette M. Acevedo, Eric A. Murphy, Jianhua Huang, Lea Scheppke, C. Stockmann, Richard J. Johnson, N. Angle and 1 more. Nature, 2008

646 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/487c28a2d0b0c2807c3fc9ca6c9035bd324f3904

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Citations in the corpus

Tumor angiogenesis: molecular pathways and therapeutic targets (2011, background): “Exposing VSMC to PDGF stimulates migration and proliferation to promote coverage and stabilization of newly formed blood vessels, whereas exposure to VEGF inhibits VSMC function and suppresses PDGF-induced angiogenesi”
The roles of vascular endothelial growth factor in bone repair and regeneration (2016, background): “This leads to formation of immature blood vessels [102].”
Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions (2014, background): “These include: endothelial cells of the normal vasculature [218], dendritic cells [219], myeloid cells [220], neurons [221], pericytes [222] and tumour cells [201, 212, 223–228].”
In vitro microvessels for the study of angiogenesis and thrombosis (2012, result): “The consistently low coverage of the vessels by pericytes and the lack of a retracted state suggest that the presence of proangiogenic factors suppressed recruitment of pericytes toward the microvessels; this behavior is consistent with the observation in vivo that VEGF is a negative regulator for p”
Macrophages and therapeutic resistance in cancer (2015, neutral): “VEGF antagonists induce vascular normalization (Greenberg et al., 2008; Jain, 2005), and several studies have reported increased uptake of chemotherapeutics associated with this process, likely because of reduced vessel leakiness and interstitial fluid pressure (Chauhan et al.”
The therapeutic promise of the cancer stem cell concept. (2010, background): “Although the exact mechanisms underlying these findings remain to be elucidated, recent studies have identified important differences between inhibition of myeloid cell–derived VEGF compared with tumor-derived VEGF on tumor growth (71, 72).”
Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases (2011, background): “These effects can also be achieved using genetic approaches to ablate VEGF functio”
Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization (2009, neutral): “It remains to be determined how PHD2 interacts with other ‘‘normalization’’ pathways, such as nitric oxide, Tie2, MMPs, myeloid-derived VEGF, Rgs5, and PDGFR-b (Greenberg et al., 2008; Hamzah et al., 2008; Kashiwagi et al., 2008; Stockmann et al., 2008; Winkler et al., 2004).”
Tumor angiogenesis and vascular normalization: alternative therapeutic targets (2017, background): “Tumor cells secrete abundant VEGF, which leads to the formation of immature vessels characterized by inadequate pericyte coverage [37].”
Metastatic Stem Cells: Sources, Niches, and Vital Pathways (2014, background): “blood platelets (Bos et al., 2009; Chabottaux et al., 2009; Chen et al., 2011a; Gay and Felding-Habermann, 2011; Gocheva et al., 2010; Greenberg et al., 2008; Gupta et al., 2007; Kim et al., 2009; Labelle et al., 2011; Li et al., 2010; Padua et al., 2008; Reymond et al., 2013; Rolny et al., 2011; So”
Integrins in cancer: biological implications and therapeutic opportunities (2010, neutral): “In fact, crosstalk between growth factor receptors, such as VEGFR2 and platelet-derived growth factor receptor (PDGFR), regulates pericyte recruitment to tumour-associated blood vessel”