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首页> 外文期刊>Nature >Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.
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Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.

机译：通过Notch1的Dll4信号传导在血管生成过程中调节尖端细胞的形成。

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In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A. VEGF-A is also essential for the induction of endothelial tip cells, but it is not known how single tip cells are selected to lead each vessel sprout, and how tip-cell numbers are determined. Here we present evidence that delta-like 4 (Dll4)-Notch1 signalling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in the mouse retina. We show that inhibition of Notch signalling using gamma-secretase inhibitors, genetic inactivation of one allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1, all promote increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 peptide leads to fewer tip cells and vessel branches. Dll4 and reporters of Notch signalling are distributed in a mosaic pattern among endothelial cells of activelysprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assume tip-cell characteristics. Together, our results suggest that Dll4-Notch1 signalling between the endothelial cells within the angiogenic sprout serves to restrict tip-cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. This model offers an explanation for the dose-dependency and haploinsufficiency of the Dll4 gene, and indicates that modulators of Dll4 or Notch signalling, such as gamma-secretase inhibitors developed for Alzheimer's disease, might find usage as pharmacological regulators of angiogenesis.
机译：在发芽血管生成中，专门的内皮尖端细胞将血管芽的生长引向血管内皮生长因子（VEGF）-A的梯度。 VEGF-A对于诱导内皮尖端细胞也是必不可少的，但是尚不清楚如何选择单个尖端细胞来引导每个血管发芽，以及如何确定尖端细胞的数目。在这里，我们提供的证据表明，δ-样4（Dll4）-Notch1信号调节了适当数量的尖端细胞的形成，以控制小鼠视网膜中血管的萌芽和分支。我们显示，使用Notch信号抑制γ分泌酶抑制剂，内皮Notch配体Dll4的一个等位基因的遗传失活或Notch1的内皮特异性遗传缺失，都促进了尖端细胞数量的增加。相反，可溶的锯齿状1肽对Notch的激活导致末端细胞和血管分支减少。 Dll4和Notch信号的报告基因以马赛克的方式分布在主动发芽的视网膜血管的内皮细胞之间。在此位置，Notch1缺失的内皮细胞优先呈现尖端细胞特征。在一起，我们的结果表明，在血管新生芽内的内皮细胞之间的Dll4-Notch1信号转导用于限制响应VEGF的梢细胞形成，从而在正确的萌芽和分支模式所需的梢细胞和茎细胞之间建立足够的比例。该模型为Dll4基因的剂量依赖性和单倍剂量不足提供了解释，并表明Dll4或Notch信号传导的调节剂（例如为阿尔茨海默氏病开发的伽玛分泌酶抑制剂）可能会用作血管生成的药理调节剂。

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