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

  • 120 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.

LanguageEnglish (US)
Pages192-197
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. 2015 ; Vol. 520, No. 7546. pp. 192-197
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