A role for VEGF as a negative regulator of pericyte function and vessel maturation.
A role for VEGF as a negative regulator of pericyte function and vessel maturation.
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DOI：
10.1038/nature07424
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发表时间：
2008-12-11
期刊：
影响因子：
64.8
通讯作者：
Cheresh, David A.
中科院分区：
文献类型：
--
作者：
Greenberg, Joshua I.;Shields, David J.;Barillas, Samuel G.;Acevedo, Lisette M.;Murphy, Eric;Huang, Jianhua;Scheppke, Lea;Stockmann, Christian;Johnson, Randall S.;Angle, Niren;Cheresh, David A.
血管生成不仅依赖于内皮细胞的入侵和增殖：它还需要周细胞覆盖血管萌芽以稳定血管。血管内皮生长因子(VEGF)和血小板衍生生长因子(PDGF)分别通过其在内皮细胞和血管平滑肌细胞(VSMCs)上的同源受体来协调这些过程。PDGF通过启动VSMCs/周细胞释放促血管生成介质来诱导新生血管形成。虽然血管内皮生长因子直接刺激内皮细胞的增殖和迁移，但其在周细胞生物学中的作用尚不清楚。在这里，我们根据血管内皮生长因子干扰血管平滑肌细胞功能的能力，将其定义为新生血管的抑制因子。具体地说，在PDGF介导的血管生成条件下，血管内皮生长因子去除新生血管萌芽的周细胞覆盖，导致血管不稳定。在分子水平上，血管内皮生长因子介导的血管内皮生长因子-R2的激活通过组装一个先前未被描述的由血小板衍生生长因子受体β和血管内皮生长因子-R2组成的受体复合体来抑制血管平滑肌细胞中的血小板衍生生长因子受体β信号转导。抑制血管内皮生长因子-R2不仅阻止这种受体复合体的组装，而且还能恢复暴露于血管内皮生长因子和PDGF的组织中的血管生成。最后，肿瘤细胞血管内皮生长因子的基因缺失破坏了血小板衍生生长因子受体β/血管内皮生长因子R2复合体的形成，促进了肿瘤血管的成熟。这些发现强调了VSMCs/周细胞在新生血管形成中的重要性，并揭示了作为内皮细胞功能的促进者和VSMCs和血管成熟的负调节因子的血管内皮生长因子和血管内皮生长因子-R2信号的双重作用。
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.
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