Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Endocrinology & Metabolism, BINDING PROTEIN 4, OXIDATIVE STRESS, DYSFUNCTION, METABOLISM, METASTASIS, INHIBITION, BIOMARKER, GLUTAMINE, ARREST, CPT1A, angiogenesis, endothelial cell dysfunction, endothelial cells, fatty acid β-oxidation, metabolism, quiescence, redox homeostasis, Animals, Carnitine O-Palmitoyltransferase, Cell Proliferation, Energy Metabolism, Fatty Acids, HEK293 Cells, Homeostasis, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Inbred C57BL, NADP, Oxidation-Reduction, Oxidative Stress, Receptor, Notch1, TECNEC - 743074;info:eu-repo/grantAgreement/EC/H2020/743074, METH/14/08#53009403, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 3101 Biochemistry and cell biology, 3205 Medical biochemistry and metabolomics

Abstract:

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.