Control of endothelial quiescence by FOXO-regulated metabolites.
Détails
Télécharger: 33795871_BIB_FD68345F21FB.pdf (10892.97 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_FD68345F21FB
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Control of endothelial quiescence by FOXO-regulated metabolites.
Périodique
Nature cell biology
ISSN
1476-4679 (Electronic)
ISSN-L
1465-7392
Statut éditorial
Publié
Date de publication
04/2021
Peer-reviewed
Oui
Volume
23
Numéro
4
Pages
413-423
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Mots-clé
Animals, Cell Proliferation/genetics, Endothelial Cells/metabolism, Forkhead Box Protein O1/genetics, Gene Expression Regulation/genetics, Glutarates/metabolism, Human Umbilical Vein Endothelial Cells/metabolism, Humans, Metabolism/genetics, Mice, Neovascularization, Physiologic/genetics, Proto-Oncogene Proteins c-akt, Signal Transduction/genetics, Valerates/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
24/04/2021 15:54
Dernière modification de la notice
11/01/2022 13:58