Metabolic Signatures of Distinct Endothelial Phenotypes

Angiogenesis is crucial for the development of the blood vasculature during embryogenesis, but also contributes to cancer and other diseases. While therapeutic targeting of endothelial cells (ECs) through growth factor inhibition is limited by insufficient efficacy and resistance, a new paradigm for modulating angiogenesis by targeting EC metabolism has emerged. Findings from the past decade highlight how ECs adapt their metabolism to proliferate or migrate during vessel sprouting, or to maintain the vascular barrier and protect themselves against oxidative stress in the high-oxygen environment they are exposed to in healthy conditions. We overview key endothelial metabolic pathways underlying the different EC phenotypes, as well as potential opportunities for targeting EC metabolism in therapeutic settings. We postulated in 2009 that the formation of new blood vessels by ECs requires adaptations of EC metabolic pathways, a concept that now has been experimentally validated.ECs exhibit remarkable plasticity both at the phenotypic and metabolic (transcriptome) levels.Preclinical studies have revealed that targeting specific EC metabolic pathways can offer antiangiogenic benefits. The challenge will be to translate these findings to the clinic.