TY - JOUR T1 - Chemical inhibition of prolyl hydroxylases impairs angiogenic competence of human vascular endothelium through metabolic reprogramming JF - bioRxiv DO - 10.1101/2022.03.25.485858 SP - 2022.03.25.485858 AU - Ratnakar Tiwari AU - Prashant V. Bommi AU - Peng Gao AU - Matthew J. Schipma AU - Yalu Zhou AU - Susan E. Quaggin AU - Navdeep S. Chandel AU - Pinelopi P. Kapitsinou Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/03/26/2022.03.25.485858.abstract N2 - Endothelial cell (EC) metabolism has emerged as a driver of angiogenesis. While hypoxia inactivates prolyl-4 hydroxylase domain containing proteins 1-3 (PHD1-3) and stabilizes hypoxia inducible factors (HIFs) stimulating angiogenesis, the effects of PHDs on EC functions remain unclear. Here, we investigated the impact of PHD inhibition by dimethyloxalylglycine (DMOG) on angiogenic competence and metabolism of human vascular ECs. PHD inhibition reduced EC proliferation, migration, and tube formation capacities. Furthermore, transcriptomic and metabolomic analyses revealed an unfavorable metabolic reprogramming for angiogenesis following treatment with DMOG. Despite the induction of glycolytic genes and high levels of lactate, multiple genes encoding sub-units of mitochondrial complex I were suppressed with concurrent decline in nicotinamide adenine dinucleotide (NAD+) levels. Importantly, defective EC migration due to DMOG could be partially restored by augmenting NAD+ levels. Combined, our data provide metabolic insights into the mechanism by which chemical PHD inhibition impairs angiogenic competence of human vascular ECs.Competing Interest StatementThe authors have declared no competing interest. ER -