1. Control of endothelial quiescence by FOXO-regulated metabolites.
- Author
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Andrade J, Shi C, Costa ASH, Choi J, Kim J, Doddaballapur A, Sugino T, Ong YT, Castro M, Zimmermann B, Kaulich M, Guenther S, Wilhelm K, Kubota Y, Braun T, Koh GY, Grosso AR, Frezza C, and Potente M
- Subjects
- Animals, Gene Expression Regulation genetics, Glutarates metabolism, Human Umbilical Vein Endothelial Cells metabolism, Humans, Metabolism genetics, Mice, Proto-Oncogene Proteins c-akt, Signal Transduction genetics, Valerates metabolism, Cell Proliferation genetics, Endothelial Cells metabolism, Forkhead Box Protein O1 genetics, Neovascularization, Physiologic genetics
- Abstract
Endothelial cells (ECs) adapt their metabolism to enable the growth of new blood vessels, but little is known how ECs regulate metabolism to adopt a quiescent state. Here, we show that the metabolite S-2-hydroxyglutarate (S-2HG) plays a crucial role in the regulation of endothelial quiescence. We find that S-2HG is produced in ECs after activation of the transcription factor forkhead box O1 (FOXO1), where it limits cell cycle progression, metabolic activity and vascular expansion. FOXO1 stimulates S-2HG production by inhibiting the mitochondrial enzyme 2-oxoglutarate dehydrogenase. This inhibition relies on branched-chain amino acid catabolites such as 3-methyl-2-oxovalerate, which increase in ECs with activated FOXO1. Treatment of ECs with 3-methyl-2-oxovalerate elicits S-2HG production and suppresses proliferation, causing vascular rarefaction in mice. Our findings identify a metabolic programme that promotes the acquisition of a quiescent endothelial state and highlight the role of metabolites as signalling molecules in the endothelium.
- Published
- 2021
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