Control of vessel sprouting by genetic and metabolic determinants

• The role of endothelial cell (EC) metabolism in vascular branching is not understood.
• Vessel branching requires the coordinated action of distinct EC subtypes.
• PFKFB3-driven glycolysis in ECs determines tip versus stalk cell fate.

Vessel sprouting by endothelial cells (ECs) during angiogenesis relies on a navigating tip cell and on proliferating stalk cells that elongate the shaft. To date, only genetic signals have been shown to regulate vessel sprouting. However, emerging evidence indicates that the angiogenic switch also requires a metabolic switch. Indeed, angiogenic signals not only induce a change in EC metabolism but this metabolic adaptation also co-determines vessel sprouting. The glycolytic activator PFKFB3 regulates stalk cell proliferation and renders ECs more competitive to reach the tip. We discuss the emerging link between angiogenesis and EC metabolism during the various stages of vessel sprouting, focusing only on genetic signals for which an effect on EC metabolism has been documented.