How glucose, glutamine and fatty acid metabolism shape blood and lymph vessel development.

Recently, endothelial cell metabolism has emerged as an essential driver and regulator of both blood and lymph vessel development. Evidence rapidly builds that metabolism is not only necessary for endothelial cell function, but moreover controls several aspects of the (lymph)-angiogenic process. So far, the best-characterized metabolic pathways to have an impact on angiogenesis are glycolysis, fatty acid oxidation and glutamine metabolism. Glycolysis regulates tip cell behavior by providing ATP, fatty acid oxidation controls stalk cell proliferation by producing nucleotide biomass, and glutamine metabolism is critical for tip and stalk cell dynamics by supporting Krebs cycle anaplerosis, protein production and redox homeostasis, and links to asparagine metabolism. During lymphangiogenesis, glycolysis and fatty acid oxidation are key metabolic pathways. Glycolysis provides energy for growing lymph vessels, while fatty acid oxidation is a critical metabolic regulator of lymphangiogenesis, in part by promoting nucleotide synthesis as well as by mediating epigenetic changes of histone acetylation, which promotes transcription of key lymphatic genes, and hence venous-to-lymphatic endothelial cell differentiation. On the whole, increasing knowledge on the metabolic landscape of endothelial cells offers a fresh impetus to future treatment possibilities of vascular related diseases.