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Control of endothelial quiescence by FOXO-regulated metabolites

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Item Type:Article
Title:Control of endothelial quiescence by FOXO-regulated metabolites
Creators Name:Andrade, J. and Shi, C. and Costa, A.S.H. and Choi, J. and Kim, J. and Doddaballapur, A. and Sugino, T. and Ong, Y.T. and Castro, M. and Zimmermann, B. and Kaulich, M. and Guenther, S. and Wilhelm, K. and Kubota, Y. and Braun, T. and Koh, G.Y. and Grosso, A.R. and Frezza, C. and Potente, M.
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.
Keywords:Animals, Mice
Source:Nature Cell Biology
ISSN:1465-7392
Publisher:Nature Publishing Group
Volume:23
Page Range:413-423
Date:April 2021
Official Publication:https://doi.org/10.1038/s41556-021-00637-6
PubMed:View item in PubMed

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