Chemical inhibition of oxygen-sensing prolyl hydroxylases impairs angiogenic competence of human vascular endothelium through metabolic reprogramming

Endothelial cell (EC) metabolism has emerged as a driver of angiogenesis. While hypoxia inactivates the oxygen sensors prolyl-4 hydroxylase domain-containing proteins 1-3 (PHD1-3) and stimulates angiogenesis, the effects of PHDs on EC functions remain poorly defined. Here, we investigated the impact of chemical PHD inhibition by dimethyloxalylglycine (DMOG) on angiogenic competence and metabolism of human vascular ECs. DMOG reduced EC proliferation, migration, and tube formation capacities, responses that were associated with an unfavorable metabolic reprogramming. While glycolytic genes were induced, multiple genes encoding sub-units of mitochondrial complex I were suppressed with con-current decline in nicotinamide adenine dinucleotide (NAD(+)) levels. Importantly, the DMOG-induced defects in EC migration could be partially rescued by augmenting NAD(+) levels through nicotinamide riboside or citrate supplementation. In summary, by integrating functional assays, transcriptomics, and metabolomics, we provide insights into the effects of PHD inhibition on angiogenic competence and metabolism of human vascular ECs.

Automated summary

The impact of chemical PHD inhibition by DMOG on angiogenic competence and metabolism of human vascular ECs was investigated. The results showed that DMOG reduced cell proliferation, migration, and tube formation capacities, and led to an unfavorable metabolic reprogramming. The DMOG-induced defects in cell migration could be partially rescued by augmenting NAD(+) levels.