Title: Fatty acid carbon is essential for dNTP synthesis in endothelial cells
Authors: Schoors, Sandra
Bruning, Ulrike
Missiaen, Rindert
Queiroz, Karla C S
Borgers, Gitte
Elia, Ilaria
Zecchin, Annalisa
Cantelmo, Anna Rita
Christen, Stefan
Goveia, Jermaine
Heggermont, Ward
Goddé, Lucica
Vinckier, Stefan
Van Veldhoven, Paul P
Eelen, Guy
Schoonjans, Luc
Gerhardt, Holger
Dewerchin, Mieke
Baes, Myriam
De Bock, Katrien
Ghesquière, Bart
Lunt, Sophia Y
Fendt, Sarah-Maria #
Carmeliet, Peter # ×
Issue Date: 9-Apr-2015
Publisher: Nature Publishing Group
Series Title: Nature vol:520 issue:7546 pages:192-7
Article number: 10.1038/nature14362
Abstract: The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis.
ISSN: 0028-0836
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Cellular Metabolism and Metabolic Regulation (VIB-KU Leuven Centre for Cancer Biology) (+)
Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven Centre for Cancer Biology) (+)
Laboratory for Mechanisms of Cell Transformation (VIB-KU Leuven Centre for Cancer Biology)
Laboratory of Lipid Biochemistry and Protein Interactions
Vascular Patterning Laboratory (VIB-KU Leuven Centre for Cancer Biology) (+)
Cell Metabolism
Exercise Physiology Research Group
× corresponding author
# (joint) last author

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