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Fatty acid carbon is essential for dNTP synthesis in endothelial cells
Open accessAbstract
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.
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“Acetyl CoA from FAO is used for the TCA cycle as well as for aspartate and nucleotide synthesis.52”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [52]
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Metadata
- Authors
- Schoors, S., Bruning, U., Missiaen, R., Queiroz, K. C. S., Borgers, G., Elia, I., Zecchin, A., Cantelmo, A. R., Christen, S., Goveia, J., Heggermont, W., Goddé, L., Vinckier, S., Van Veldhoven, P. P., Eelen, G., Schoonjans, L., Gerhardt, H., Dewerchin, M., Baes, M., De Bock, K., Ghesquière, B., Lunt, S. Y., Fendt, S.-M., & Carmeliet, P.
- Affiliations
- KU Leuven (BE)
- Universitair Ziekenhuis Leuven (BE)
- Max Delbrück Center (DE)
- Michigan State University (US)
- Corresponding author
- Fendt, Sarah-Maria
- Carmeliet, Peter
- ORCID
- Venue
- Nature
- Published
- 2015-04-01
- Volume
- 520
- Issue
- 7546
- Pages
- 192-197
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4413024
- OpenAlex
- W2075209047
- Cited by
- 646
- References
- 37
- Citations by year
- 2026: 50 · 2025: 65 · 2024: 78 · 2023: 39 · 2022: 66 · 2021: 55 · 2020: 68 · 2019: 45 · 2018: 61 · 2017: 55 · 2016: 43 · 2015: 19
- FWCI
- 19.61
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-08-05)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- fatty acid oxidation, CPT1A, endothelial cells, angiogenesis, vessel sprouting, de novo nucleotide synthesis, dNTP synthesis, aspartic acid, uridine monophosphate, acetyl-CoA, TCA cycle, endothelial cell proliferation, pathological angiogenesis, retinopathy of prematurity, ocular angiogenesis
- MeSH terms
- Adenosine Triphosphate, Animals, Blood Vessels, Carbon, Carnitine O-Palmitoyltransferase, Citric Acid Cycle, Disease Models, Animal, DNA, Fatty Acids, Glucose, Humans, Neovascularization, Pathologic, Nucleotides, Oxidation-Reduction, Retinopathy of Prematurity, Acetic Acid, Gene Silencing, Endothelial Cells, Cell Line, Tumor, Cell Proliferation, Mice, Human Umbilical Vein Endothelial Cells
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