Control of endothelial quiescence by FOXO-regulated metabolites.
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