Chemical inhibition of oxygen-sensing prolyl hydroxylases impairs angiogenic competence of human vascular endothelium through metabolic reprogramming
Year: 2022
Type: article
Abstract: ABSTRACT 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.
Source: iScience
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,000
Awards: Pathogenesis of Diabetic Nephropathy, Harnessing hypoxia responses to treat postischemic kidney injury and inflammation, G1860631916, G2921881625, Kidney Therapeutics: Translating Discoveries into Prevention, Treatment and Cures for Kidney Diseases, G7285114270, G8838538855, G9000150948, Kansas IDeA Network of Biomedical Research Excellence 5, Endothelial oxygen sensing and metabolic reprogramming in AKI to CKD transition
OpenAlex ID: W4294733803