Chemical inhibition of oxygen-sensing prolyl hydroxylases impairs angiogenic competence of human vascular endothelium through metabolic reprogramming
Ratnakar Tiwari,
Prashant V. Bommi,
Peng Gao,
Matthew J. Schipma,
Yalu Zhou,
Susan E. Quaggin,
Navdeep S. Chandel,
Pinelopi P. Kapitsinou
Affiliations
Ratnakar Tiwari
Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 East Superior Street, SQBRC 8-408, Chicago, 60611 IL, USA; Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Prashant V. Bommi
Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 East Superior Street, SQBRC 8-408, Chicago, 60611 IL, USA; Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Peng Gao
Department of Medicine and Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Matthew J. Schipma
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Yalu Zhou
Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 East Superior Street, SQBRC 8-408, Chicago, 60611 IL, USA; Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Susan E. Quaggin
Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 East Superior Street, SQBRC 8-408, Chicago, 60611 IL, USA; Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Navdeep S. Chandel
Department of Medicine and Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Pinelopi P. Kapitsinou
Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 East Superior Street, SQBRC 8-408, Chicago, 60611 IL, USA; Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Medicine and Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Corresponding author
Summary: 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 concurrent 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.
