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Fatty acid carbon is essential for dNTP synthesis in endothelial cells

Item Type:Article
Title:Fatty acid carbon is essential for dNTP synthesis in endothelial cells
Creators Name:Schoors, S. and Bruning, U. and Missiaen, R. and Queiroz, K.C.S. and Borgers, G. and Elia, I. and Zecchin, A. and Cantelmo, A.R. and Christen, S. and Goveia, J. and Heggermont, W. and Godde, L. and Vinckier, S. and Van Veldhoven, P.P. and Eelen, G. and Schoonjans, L. and Gerhardt, H. and Dewerchin, M. and Baes, M. and De Bock, K. and Ghesquiere, B. and Lunt, S.Y. and Fendt, S.M. and Carmeliet, P.
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.
Keywords:Acetic Acid, Adenosine Triphosphate, Animal Disease Models, Blood Vessels, Carbon, Carnitine O-Palmitoyltransferase, Cell Proliferation, Citric Acid Cycle, DNA, Endothelial Cells, Fatty Acids, Gene Silencing, Glucose, Human Umbilical Vein Endothelial Cells, Nucleotides, Oxidation-Reduction, Pathologic Neovascularization, Retinopathy of Prematurity, Tumor Cell Line, Animals, Mice
Source:Nature
ISSN:0028-0836
Publisher:Nature Publishing Group (U.K.)
Volume:520
Number:7546
Page Range:192-197
Date:9 April 2015
Additional Information:Erratum in: Nature 526(7571): 144.
Official Publication:https://doi.org/10.1038/nature14362
PubMed:View item in PubMed

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