Fatty acid carbon is essential for dNTP synthesis in endothelial cells

Sandra Schoors, Ulrike Bruning, Rindert Missiaen, Karla C. S. Queiroz, Gitte Borgers, Ilaria Elia, Annalisa Zecchin, Anna Rita Cantelmo, Stefan Christen, Jermaine Goveia, Ward Heggermont, Lucica Goddé, Stefan Vinckier, Paul P. Van Veldhoven, Guy Eelen, Luc Schoonjans, Holger Gerhardt, Mieke Dewerchin, Myriam Baes, Katrien De Bock, Bart Ghesquière, Sophia Y. Lunt, Sarah-Maria Fendt () and Peter Carmeliet ()
Additional contact information
Sandra Schoors: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Ulrike Bruning: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Rindert Missiaen: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Karla C. S. Queiroz: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Gitte Borgers: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Ilaria Elia: Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven, B-3000 Leuven, Belgium
Annalisa Zecchin: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Anna Rita Cantelmo: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Stefan Christen: Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven, B-3000 Leuven, Belgium
Jermaine Goveia: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Ward Heggermont: Center for Molecular & Vascular Biology, KU Leuven
Lucica Goddé: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Stefan Vinckier: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Paul P. Van Veldhoven: Laboratory of Lipid Biochemistry and Protein Interactions, KU Leuven, B-3000 Leuven, Belgium
Guy Eelen: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Luc Schoonjans: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Holger Gerhardt: Vascular Patterning Laboratory, KU Leuven, B-3000 Leuven, Belgium
Mieke Dewerchin: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Myriam Baes: Laboratory of Cell Metabolism, KU Leuven, B-3000 Leuven, Belgium
Katrien De Bock: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Bart Ghesquière: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
Sophia Y. Lunt: Michigan State University
Sarah-Maria Fendt: Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven, B-3000 Leuven, Belgium
Peter Carmeliet: Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium

Nature, 2015, vol. 520, issue 7546, 192-197

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14362

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