Control of endothelial quiescence by FOXO-regulated metabolites.
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
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
05
02
2020
accepted:
21
01
2021
pubmed:
3
4
2021
medline:
29
6
2021
entrez:
2
4
2021
Statut:
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.
Identifiants
pubmed: 33795871
doi: 10.1038/s41556-021-00637-6
pii: 10.1038/s41556-021-00637-6
pmc: PMC8032556
doi:
Substances chimiques
Forkhead Box Protein O1
0
Glutarates
0
Valerates
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
413-423Subventions
Organisme : Medical Research Council
ID : MRC_MC_UU_12022/6
Pays : United Kingdom
Organisme : European Research Council
ID : 773047
Pays : International
Organisme : Medical Research Council
ID : MC_UU_12022/6
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1101/3
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA045508
Pays : United States
Commentaires et corrections
Type : CommentIn
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