To form new blood vessels (angiogenesis), endothelial cells (ECs) must be activated and acquire highly migratory and proliferative phenotypes. However, the molecular mechanisms that govern these processes are incompletely understood. Here, we show that Apelin signaling functions to drive ECs into such an angiogenic state. Zebrafish lacking Apelin signaling exhibit defects in endothelial tip cell morphology and sprouting. Using transplantation experiments, we find that in mosaic vessels, wild-type ECs leave the dorsal aorta (DA) and form new vessels while neighboring ECs defective in Apelin signaling remain in the DA. Mechanistically, Apelin signaling enhances glycolytic activity in ECs at least in part by increasing levels of the growth-promoting transcription factor c-Myc. Moreover, APELIN expression is regulated by Notch signaling in human ECs, and its function is required for the hypersprouting phenotype in Delta-like 4 (Dll4) knockdown zebrafish embryos. These data provide new insights into fundamental principles of blood vessel formation and Apelin signaling, enabling a better understanding of vascular growth in health and disease.

中文翻译：

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Apelin 信号驱动血管内皮细胞进入促血管生成状态

为了形成新血管（血管生成），内皮细胞 (EC) 必须被激活并获得高度迁移和增殖的表型。然而，控制这些过程的分子机制尚不完全清楚。在这里，我们展示了 Apelin 信号传导功能可以驱动 ECs 进入这种血管生成状态。缺乏 Apelin 信号的斑马鱼在内皮尖端细胞形态和发芽方面表现出缺陷。使用移植实验，我们发现在镶嵌血管中，野生型 ECs 离开背主动脉 (DA) 并形成新血管，而在 Apelin 信号传导中存在缺陷的相邻 ECs 保留在 DA 中。从机制上讲，Apelin 信号至少部分是通过增加促进生长的转录因子 c-Myc 的水平来增强 EC 中的糖酵解活性。此外，APELIN 的表达受人类 ECs 中 Notch 信号的调节，并且它的功能是 Delta-like 4 (Dll4) 敲低斑马鱼胚胎中超萌发表型所必需的。这些数据为血管形成和 Apelin 信号传导的基本原理提供了新的见解，有助于更好地了解健康和疾病中的血管生长。