First Author | Andrade J | Year | 2021 |
Journal | Nat Cell Biol | Volume | 23 |
Issue | 4 | Pages | 413-423 |
PubMed ID | 33795871 | Mgi Jnum | J:306790 |
Mgi Id | MGI:6709623 | Doi | 10.1038/s41556-021-00637-6 |
Citation | Andrade J, et al. (2021) Control of endothelial quiescence by FOXO-regulated metabolites. Nat Cell Biol 23(4):413-423 |
abstractText | 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. |