Quiescent endothelial cells upregulate fatty acid ß-oxidation for vasculoprotection via redox homeostasis

Little is known about metabolic changes accompanying endothelial cell (EC) quiescence. Nonetheless, when dysfunctional, quiescent ECs (QECs) contribute to multiple cardiovascular diseases. ECs need fatty acid ß-oxidation (FAO) for proliferation. Surprisingly, we now report that QECs are not hypo-metabolic, but upregulate FAO >3-fold higher than proliferating ECs (PECs), not to support biomass or energy production, but to sustain the TCA cycle for redox homeostasis through NADPH production. Hence, inhibition of FAO-controlling CPT1A promotes EC dysfunction (anti-fibrinolysis, leukocyte infiltration, barrier disruption) by increasing oxidative stress in CPT1A?EC mice with endothelial CPT1A loss. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-CoA) induces vasculoprotection against oxidative stress and EC dysfunction in CPT1A?EC mice, possibly creating therapeutic opportunities. Thus, ECs use FAO for vasculoprotection against their high oxygen (oxidative stress-prone) milieu, and for different metabolic purposes dependent on their proliferation versus quiescence status.