Control of endothelial quiescence by FOXO-regulated metabolites

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.

Chemical inhibition of prolyl hydroxylases impairs angiogenic competence of human vascular endothelium through metabolic reprogramming

“…Consistent with our findings is a recent study in which S-2-hydroxyglutarate (S-2HG), a metabolite with inhibitory effect on PHDs, lowered the proliferative capacity of EC, an effect also recapitulated by genetic PHD inactivation (54). The precise metabolic mechanism by which chemical PHD inactivation impairs proliferation of human ECs remains to be defined but probably involves inability to generate the essential metabolites for macromolecule synthesis due to suppressed mitochondrial oxidation and glutamine metabolism.…”

IL-6-induced FOXO1 activity determines the dynamics of metabolism in CD8 T cells cross-primed by liver sinusoidal endothelial cells

“…Treatment of LSECs with pharmacological inhibitors of FOXO1 or NOTCH1 signaling, both relevant for vascular development in endothelial cells (Wilhelm et al, 2016), affected neither scavenger function nor glucose uptake. Intercellular adhesion molecule (ICAM)-1 expression, however, that is a target gene of FOXO1, was downregulated by FOXO1 inhibition (Figure S1J), indicating a distinct a role for FOXO1 in microvascular LSECs compared with macrovascular endothelial cells (Andrade et al, 2021;Wilhelm et al, 2016). Together, these results indicate that constitutive highlevel mitochondrial respiration in LSECs was associated with tight mitochondrial cristae structure and supported effective scavenging functions, which were independent of FOXO1 and NOTCH1 signaling.…”

Homeostatic maintenance of the lymphatic vasculature

“…Another key regulator of BEC quiescence is the FOXO1 transcription factor that is inactivated in proliferating cells by PI3K-protein kinase B (AKT)-induced phosphorylation. FOXO1 suppresses MYC signaling and regulates a metabolic program that promotes quiescence in BECs [90,91]; however, whether it has a similar role in LECs is not known.…”