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, and its function is required for the hypersprouting phenotype in Delta-like 4 (Dll4) knockdown 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.

The establishment of a functional cardiovascular system is crucial for the development of all vertebrates. Defects in the development of the cardiovascular system lead to cardiovascular diseases, which are among the top 10 causes of death worldwide. However, we are just beginning to understand which signaling pathways guide blood vessel growth in different tissues and organs. The advantages of the model organism zebrafish (Danio rerio) helped to identify novel cellular and molecular mechanisms of vascular growth. In this review we will discuss the current knowledge of vasculogenesis and angiogenesis in the zebrafish embryo. In particular, we describe the molecular mechanisms that contribute to the formation of blood vessels in different vascular beds within the embryo.

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