Quiescent Endothelial Cells Upregulate Fatty Acid β-Oxidation for Vasculoprotection via Redox Homeostasis
2 LKI - Leuven Cancer Institute [Leuven, Belgium]
3 VIB-CCB - Laboratory of Angiogenesis and Vascular Metabolism [Leuven, Belgium]
4 SYSU - Sun Yat-sen University [Guangzhou]
5 BIH - Berlin Institute of Health
6 UCLouvain - Université Catholique de Louvain = Catholic University of Louvain
7 LDRI - Louvain Drug Research Institute [Bruxelles, Belgique]
8 VIB-KU Leuven | CFM - VIB-KU Leuven Center for Microbiology
9 UZH - Universität Zürich [Zürich] = University of Zurich
10 BRI - Brain Research Institute
11 University of Leeds
12 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
Résumé
Little is known about the metabolism of quiescent endothelial cells (QECs). Nonetheless, when dysfunctional, QECs contribute to multiple diseases. Previously, we demonstrated that proliferating endothelial cells (PECs) use fatty acid β-oxidation (FAO) for de novo dNTP synthesis. We report now that QECs are not hypometabolic, but upregulate FAO >3-fold higher than PECs, not to support biomass or energy production but to sustain the tricarboxylic acid cycle for redox homeostasis through NADPH regeneration. Hence, endothelial loss of FAO-controlling CPT1A in CPT1AΔEC mice promotes EC dysfunction (leukocyte infiltration, barrier disruption) by increasing endothelial oxidative stress, rendering CPT1AΔEC mice more susceptible to LPS and inflammatory bowel disease. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-coenzyme A) restores endothelial quiescence and counters oxidative stress-mediated EC dysfunction in CPT1AΔEC mice, offering therapeutic opportunities. Thus, QECs use FAO for vasculoprotection against oxidative stress-prone exposure.