Control of endothelial quiescence by FOXO-regulated metabolites.

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Shi, Chenyue 
Choi, Jeongwoon 

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.


Funder: - Cancer Center Support Grant 5P30CA045508

Funder: - Medical Research Council (MRC_MC_UU_12022/6)

Funder: - Max Planck Society - European Research Council (ERC) Consolidator Grant EMERGE (773047) - European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie action (814316) - Deutsche Forschungsgemeinschaft (SFB 834) - Cardio-Pulmonary Institute (EXC 2026, Project ID: 390649896) - DZHK (German Center for Cardiovascular Research) - Foundation Leducq Transatlantic Network - Stiftung Charité - European Molecular BiologyOrganization (EMBO) Young Investigator Programme

Animals, Cell Proliferation, Endothelial Cells, Forkhead Box Protein O1, Gene Expression Regulation, Glutarates, Human Umbilical Vein Endothelial Cells, Humans, Metabolism, Mice, Neovascularization, Physiologic, Proto-Oncogene Proteins c-akt, Signal Transduction, Valerates
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Nat Cell Biol
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Springer Science and Business Media LLC
Medical Research Council (MC_UU_12022/6)