Control of endothelial quiescence by FOXO-regulated metabolites

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Andrade et al. show that FOXO1 regulates mitochondrial metabolism to stimulate the production of the metabolite S-2HG to promote acquisition of a quiescent endothelial state. 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.
Publisher
NATURE RESEARCH
Issue Date
2021-04
Language
English
Article Type
Article
Citation

NATURE CELL BIOLOGY, v.23, no.4, pp.413 - U210

ISSN
1465-7392
DOI
10.1038/s41556-021-00637-6
URI
http://hdl.handle.net/10203/283672
Appears in Collection
MSE-Journal Papers(저널논문)
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