Control of endothelial quiescence by FOXO-regulated metabolites

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<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>S</jats:italic>-2-hydroxyglutarate (<jats:italic>S</jats:italic>-2HG) plays a crucial role in the regulation of endothelial quiescence. We find that <jats:italic>S</jats:italic>-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 <jats:italic>S</jats:italic>-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 <jats:italic>S</jats:italic>-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.</jats:p>

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  • Nature Cell Biology

    Nature Cell Biology 23 (4), 413-423, 2021-04

    Springer Science and Business Media LLC

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