Angiogenic sprouting needs to be tightly controlled. It has been suggested that the Notch ligand dll4 expressed in leading tip cells restricts angiogenesis by activating Notch signalling in trailing stalk cells. Here, we show using live imaging in zebrafish that activation of Notch signalling is rather required in tip cells. Notch activation initially triggers expression of the chemokine receptor cxcr4a. This allows for proper tip cell migration and connection to the pre-existing arterial circulation, ultimately establishing functional arterial–venous blood flow patterns. Subsequently, Notch signalling reduces cxcr4a expression, thereby preventing excessive blood vessel growth. Finally, we find that Notch signalling is dispensable for limiting blood vessel growth during venous plexus formation that does not generate arteries. Together, these findings link the role of Notch signalling in limiting angiogenesis to its role during artery formation and provide a framework for our understanding of the mechanisms underlying blood vessel network expansion and maturation.

中文翻译：

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内皮Notch信号通过控制动脉形成限制血管生成

血管新生需要严格控制。已经提出，在前导尖端细胞中表达的Notch配体dll4通过激活尾随茎细胞中的Notch信号传导来限制血管生成。在这里，我们显示了在斑马鱼中使用实时成像显示，Notch信号的激活在尖端细胞中是必需的。Notch激活最初会触发趋化因子受体cxcr4a的表达。这允许适当的尖端细胞迁移并连接到先前存在的动脉循环，最终建立功能性的动脉-静脉血流模式。随后，Notch信令减少了cxcr4a表达，从而防止过度的血管生长。最后，我们发现，Notch信号对于限制不产生动脉的静脉丛形成过程中的血管生长是必不可少的。总之，这些发现将Notch信号在限制血管生成中的作用与其在动脉形成过程中的作用联系在一起，并为我们理解血管网络扩张和成熟的机制提供了框架。