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Control of endothelial quiescence by FOXO-regulated metabolites.

Nature cell biology (2021-04-03)
Jorge Andrade, Chenyue Shi, Ana S H Costa, Jeongwoon Choi, Jaeryung Kim, Anuradha Doddaballapur, Toshiya Sugino, Yu Ting Ong, Marco Castro, Barbara Zimmermann, Manuel Kaulich, Stefan Guenther, Kerstin Wilhelm, Yoshiaki Kubota, Thomas Braun, Gou Young Koh, Ana Rita Grosso, Christian Frezza, Michael Potente
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
(±)-3-Methyl-2-oxovaleric acid sodium salt
Sigma-Aldrich
DMOG, ≥98% (HPLC)
Sigma-Aldrich
Dimethyl sulfoxide, ≥99.5% (GC), suitable for plant cell culture
Sigma-Aldrich
InSolution Cycloheximide - CAS 66-81-9 - Calbiochem, InSolution Cycloheximide, CAS 66-81-9, is a 100 mg/ml, sterile-filtered solution of Cycloheximide (Cat. No. 239763) in DMSO. An antifungal antibiotic that inhibits protein synthesis in eukaryotes.
Sigma-Aldrich
Chloroquine diphosphate salt, powder or crystals, 98.5-101.0% (EP)
Sigma-Aldrich
Dimethyl 2-oxoglutarate, 96%