Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis
Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis
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DOI：
10.1038/nature05571
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发表时间：
2007-02-15
期刊：
影响因子：
64.8
通讯作者：
Betsholtz, Christer
中科院分区：
文献类型：
--
作者：
Hellstroem, Mats;Phng, Li-Kun;Betsholtz, Christer
在萌芽血管生成中，特化的内皮尖端细胞引导血管芽向血管内皮生长因子（VEGF）-A的梯度生长（1，2）。VEGF-A对于内皮尖端细胞的诱导也是必不可少的（2），但尚不清楚如何选择单个尖端细胞来引导每个血管出芽，以及尖端细胞数量如何确定。在这里，我们提出的证据表明，三角洲样4（Dll 4）-Notch 1信号调节适当数量的尖端细胞的形成，以控制血管发芽和小鼠视网膜中的分支。我们发现，使用γ-分泌酶抑制剂抑制Notch信号传导，内皮Notch配体Dll 4的一个等位基因的遗传失活，或Notch 1的内皮特异性遗传缺失，都促进尖端细胞数量的增加。相反，可溶性锯齿1肽激活Notch会导致尖端细胞和血管分支减少。Dll 4和Notch信号转导的报告基因以马赛克模式分布在活跃出芽的视网膜血管的内皮细胞中。在这个位置，Notch 1缺失的内皮细胞优先呈现尖端细胞特征。总之，我们的研究结果表明，Dll 4-Notch 1信号之间的血管生成芽内的内皮细胞用于限制尖端细胞的形成响应VEGF，从而建立正确的发芽和分支模式所需的尖端和柄细胞之间的适当比例。该模型为Dll 4基因的剂量依赖性和单倍不足提供了解释（3-5），并表明Dll 4或Notch信号传导的调节剂，例如为阿尔茨海默病开发的γ-分泌酶抑制剂，可能用作血管生成的药理学调节剂。
In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A(1,2). VEGF-A is also essential for the induction of endothelial tip cells(2), 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 actively sprouting 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(3-5), 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.