Quiescent Endothelial Cells Upregulate Fatty Acid β-Oxidation for Vasculoprotection via Redox Homeostasis

Joanna Kalucka, Laura Bierhansl, Nadine Vasconcelos Conchinha, Rindert Missiaen, Ilaria Elia, Ulrike Brüning, Samantha Scheinok, Lucas Treps, Anna Rita Cantelmo, Charlotte Dubois, Pauline de Zeeuw, Jermaine Goveia, Annalisa Zecchin, Federico Taverna, Francisco Morales-Rodriguez, Aleksandra Brajic, Lena-Christin Conradi, Sandra Schoors, Ulrike Harjes, Kim VriensGregor-Alexander Pilz, Rongyuan Chen, Richard Cubbon, Bernard Thienpont, Bert Cruys, Brian W Wong, Bart Ghesquière, Mieke Dewerchin, Katrien De Bock, Xavier Sagaert, Sebastian Jessberger, Elizabeth A V Jones, Bernard Gallez, Diether Lambrechts, Massimiliano Mazzone, Guy Eelen, Xuri Li, Sarah-Maria Fendt, Peter Carmeliet

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)881-894.e13
JournalCell Metabolism
Volume28
Issue number6
DOIs
Publication statusPublished - 4 Dec 2018
Externally publishedYes

Keywords

  • Animals
  • Carnitine O-Palmitoyltransferase/metabolism
  • Cell Proliferation
  • Energy Metabolism
  • Fatty Acids/metabolism
  • HEK293 Cells
  • Homeostasis
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • NADP/metabolism
  • Oxidation-Reduction
  • Oxidative Stress
  • Receptor, Notch1/metabolism

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