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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching
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The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching

机译：Notch配体Delta-like 4负调控内皮尖细胞的形成和血管分支

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摘要

Delta-like 4 (Dll4) is a transmembrane ligand for Notch receptors that is expressed in arterial blood vessels and sprouting endothelial cells. Here we show that Dll4 regulates vessel branching during development by inhibiting endothelial tip cell formation. Heterozygous deletion of dll4 or pharmacological inhibition of Notch signaling using γ-secretase inhibitor revealed a striking vascular phenotype, with greatly increased numbers of f ilopodia-extending endothelial tip cells and increased expression of tip cell marker genes compared with controls. Filopodia extension in dll4~(+/-) retinal vessels required the vascular growth factor VEGF and was inhibited when VEGF signaling was blocked. Although VEGF expression was not significantly altered in dll4~(+/-) retinas, dll4~(+/-) vessels showed increased expression of VEGF receptor 2 and decreased expression of VEGF receptor 1 compared with wild-type, suggesting they could be more responsive to VEGF stimulation. In addition, expression of dll4 in wild-type tip cells was itself decreased when VEGF signaling was blocked, indicating that dll4 may act downstream of VEGF as a "brake" on VEGF-mediated angiogenic sprouting. Taken together, these data reveal Dll4 as a negative regulator of vascular sprouting and vessel branching that is required for normal vascular network formation during development.
机译：Delta-like 4（Dll4）是Notch受体的跨膜配体，在动脉血管和发芽的内皮细胞中表达。在这里，我们显示Dll4通过抑制内皮尖端细胞的形成来调节发育过程中的血管分支。与对照相比，杂合性的dll4缺失或使用γ-分泌酶抑制剂对Notch信号的药理学抑制显示了惊人的血管表型，与丝状伪足延伸的内皮尖端细胞数量相比大大增加，并且尖端细胞标记基因的表达也增加了。 dll4〜（+/-）视网膜血管中的丝足扩张需要血管生长因子VEGF，并且在VEGF信号传导被阻断时被抑制。尽管在dll4〜（+/-）视网膜中VEGF的表达没有明显改变，但与野生型相比，dll4〜（+/-）血管的VEGF受体2的表达增加，而VEGF受体1的表达减少。对VEGF刺激有反应。另外，当VEGF信号传导被阻断时，野生型梢细胞中dll4的表达本身会降低，这表明dll4可能作为VEGF介导的血管生成发芽的“刹车”而作用于VEGF的下游。综上所述，这些数据揭示了Dll4是血管发芽和血管分支的负调节剂，这是发育过程中正常血管网络形成所必需的。

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