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

Content Provider	Europe PMC
Author	Schoors, Sandra Bruning, Ulrike Missiaen, Rindert Queiroz, Karla CS 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
Abstract	The metabolism of endothelial cells (ECs) during vessel sprouting remains poorly studied. Here, we report that endothelial loss of CPT1a, a rate-limiting enzyme of fatty acid oxidation (FAO), caused vascular sprouting defects due to impaired proliferation, not migration of ECs. Reduction of FAO in ECs did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labeling studies in control ECs 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 EC 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 ECs. Finally, CPT1 blockade inhibited pathological ocular angiogenesis, suggesting a novel strategy for blocking angiogenesis.
ISSN	00280836
Volume Number	520
PubMed Central reference number	PMC4413024
Issue Number	7546
PubMed reference number	25830893
Journal	Nature
e-ISSN	14764687
DOI	10.1038/nature14362
Language	English
Publisher Date	2015-04-01
Access Restriction	Open
Rights License	Reprints and permissions information is available at www.nature.com/reprints.
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary