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 & 4 others Bart Ghesquière, Sophia Y. Lunt, Sarah Maria Fendt, Peter Carmeliet

    Research output: Contribution to journalArticle

    • 87 Citations

    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.

    Original languageEnglish (US)
    Pages (from-to)192-197
    Number of pages6
    JournalNature
    Volume520
    Issue number7546
    DOIs
    StatePublished - Apr 9 2015

    Profile

    Fatty Acids
    Carbon
    Endothelial Cells
    Acetyl Coenzyme A
    Aspartic Acid
    Nucleotides
    Pathologic Neovascularization
    Pyrimidine Nucleosides
    Deoxyribonucleosides
    Uridine Monophosphate
    Isotope Labeling
    Citric Acid Cycle
    DNA Replication
    Nucleosides
    Oxidation-Reduction
    Blood Vessels
    Acetates
    Homeostasis
    Phenotype
    DNA

    ASJC Scopus subject areas

    • General
    • Medicine(all)

    Cite this

    Schoors, S., Bruning, U., Missiaen, R., Queiroz, K. C. S., Borgers, G., Elia, I., ... Carmeliet, P. (2015). Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature, 520(7546), 192-197. DOI: 10.1038/nature14362

    Fatty acid carbon is essential for dNTP synthesis in endothelial cells. / 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.

    In: Nature, Vol. 520, No. 7546, 09.04.2015, p. 192-197.

    Research output: Contribution to journalArticle

    Schoors, S, Bruning, U, Missiaen, R, Queiroz, KCS, Borgers, G, Elia, I, Zecchin, A, Cantelmo, AR, Christen, S, Goveia, J, Heggermont, W, Goddé, L, Vinckier, S, Van Veldhoven, PP, Eelen, G, Schoonjans, L, Gerhardt, H, Dewerchin, M, Baes, M, De Bock, K, Ghesquière, B, Lunt, SY, Fendt, SM & Carmeliet, P 2015, 'Fatty acid carbon is essential for dNTP synthesis in endothelial cells' Nature, vol 520, no. 7546, pp. 192-197. DOI: 10.1038/nature14362
    Schoors S, Bruning U, Missiaen R, Queiroz KCS, Borgers G, Elia I et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature. 2015 Apr 9;520(7546):192-197. Available from, DOI: 10.1038/nature14362

    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 / Fatty acid carbon is essential for dNTP synthesis in endothelial cells.

    In: Nature, Vol. 520, No. 7546, 09.04.2015, p. 192-197.

    Research output: Contribution to journalArticle

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