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

Department of Surgery, School of Medicine, Moore's UCSD Cancer Center, USA.
Nature (Impact Factor: 41.46). 12/2008; 456(7223):809-13. DOI: 10.1038/nature07424
Source: PubMed


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-Rbeta signalling in VSMCs through the assembly of a previously undescribed receptor complex consisting of PDGF-Rbeta 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-Rbeta/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.

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    • "This may at least be partially due to the fact that anti-angiogenic drugs trigger vascular stabilization involving pericyte-coverage and that pericyte-coverage impairs further tumor vessel regression in response to anti-angiogenic treatment (26). In contrast, the presence of VEGF led to ablation of pericyte-coverage on nascent vascular sprouts and vessel de-stabilization (27). Thus, targeting pericyte recruitment, coverage and function in addition to endothelial cells may be suited to promote progress in anti-angiogenic tumor therapy (28, 29). "
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    ABSTRACT: Tumor vessels with resistance to anti-angiogenic therapy are characterized by the normalization of the vascular structures through integration of mature pericytes and smooth muscle cells (SMC) into the vessel wall, a process termed vessel stabilization. Unfortunately, stabilization-associated vascular remodeling can result in reduced sensitivity to subsequent anti-angiogenic therapy. We show here that blockade of VEGF by bevacizumab induces stabilization of angiogenic tumor blood vessels in human tumor specimen by recruiting Nestin-positive cells, whereas mature vessels down-regulated Nestin-expression. Using xenograft tumors growing on bone-marrow (BM) chimera of C57Bl/6 wildtype and Nestin-GFP transgenic mice, we show for first time that Nestin(+) cells inducing the maturation of tumor vessels do not originate from the BM but presumably reside within the adventitia of adult blood vessels. Complementary ex vivo experiments using explants of murine aortas revealed that Nestin(+) multipotent stem cells (MPSCs) are mobilized from their niche and differentiated into pericytes and SMC through the influence of tumor-cell-secreted factors. We conclude that tissue-resident Nestin(+) cells are more relevant than BM-derived cells for vessel stabilization and therefore have to be considered in future strategies for anti-angiogenic therapy. The identification of proteins mediating recruitment or differentiation of local Nestin(+) cells with potential stem cell character to angiogenic blood vessels may allow the definition of new therapeutic targets to reduce tumor resistance against anti-angiogenic drugs.
    Frontiers in Oncology 06/2014; 4:169. DOI:10.3389/fonc.2014.00169
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    • "VEGFR2 can also form direct complexes with other receptor tyrosine kinases. For example, stimulation of vascular smooth muscle cells with VEGF promotes the formation of a complex between VEGFR2 and the receptor tyrosine kinase PDGF-Rβ [222]. This results in suppression of PDGF-Rβ signalling and decreased pericyte coverage in tumours [222] and may explain the observation that, in some experimental systems, inhibition of VEGF signalling leads to increased pericyte coverage of tumour vessels and increased maturation/normalisation of the tumour vasculature [238]. "
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    ABSTRACT: Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sunitinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies.
    Angiogenesis 01/2014; 17(3). DOI:10.1007/s10456-014-9420-y · 4.88 Impact Factor
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    • "This study underscores the significance of microvascular pericyte detachment and myofibroblast transition to the development of capillary rarefaction, implicating both PDGFRβ and VEGFR2 as important mechanisms. In line with our study, Greenberg et al demonstrated that VEGF-A promoted pericyte detachment and vessel destabilization in a PDGFRβ-dependent manner.51 VEGFR2 blockade, in the condition of both VEGF-A and PDGF exposure, restores angiogenesis. "
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    ABSTRACT: Pericytes are interstitial mesenchymal cells found in many major organs. In the kidney, microvascular pericytes are defined anatomically as extensively branched, collagen-producing cells in close contact with endothelial cells. Although many molecular markers have been proposed, none of them can identify the pericytes with satisfactory specificity or sensitivity. The roles of microvascular pericytes in kidneys were poorly understood in the past. Recently, by using genetic lineage tracing to label collagen-producing cells or mesenchymal cells, the elusive characteristics of the pericytes have been illuminated. The purpose of this article is to review recent advances in the understanding of microvascular pericytes in the kidneys. In healthy kidney, the pericytes are found to take part in the maintenance of microvascular stability. Detachment of the pericytes from the microvasculature and loss of the close contact with endothelial cells have been observed during renal insult. Renal microvascular pericytes have been shown to be the major source of scar-forming myofibroblasts in fibrogenic kidney disease. Targeting the crosstalk between pericytes and neighboring endothelial cells or tubular epithelial cells may inhibit the pericyte-myofibroblast transition, prevent peritubular capillary rarefaction, and attenuate renal fibrosis. In addition, renal pericytes deserve attention for their potential to produce erythropoietin in healthy kidneys as pericytes stand in the front line, sensing the change of oxygenation and hemoglobin concentration. Further delineation of the mechanisms underlying the reduced erythropoietin production occurring during pericyte-myofibroblast transition may be promising for the development of new treatment strategies for anemia in chronic kidney disease.
    International Journal of Nephrology and Renovascular Disease 01/2014; 7:39-48. DOI:10.2147/IJNRD.S37892
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