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Fatty acid carbon is essential for dNTP synthesis in endothelial cells

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  • Sandra Schoors

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Ulrike Bruning

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Rindert Missiaen

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Karla C. S. Queiroz

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Gitte Borgers

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Ilaria Elia

    (Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Annalisa Zecchin

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Anna Rita Cantelmo

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Stefan Christen

    (Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Jermaine Goveia

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Ward Heggermont

    (Center for Molecular & Vascular Biology, KU Leuven
    Division of Clinical Cardiology, UZ Leuven, B-3000 Leuven, Belgium)

  • Lucica Goddé

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Stefan Vinckier

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Paul P. Van Veldhoven

    (Laboratory of Lipid Biochemistry and Protein Interactions, KU Leuven, B-3000 Leuven, Belgium)

  • Guy Eelen

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Luc Schoonjans

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Holger Gerhardt

    (Vascular Patterning Laboratory, KU Leuven, B-3000 Leuven, Belgium
    Vascular Patterning Laboratory, Vesalius Research Center, VIB, B-3000 Leuven, Belgium
    Integrative Vascular Biology Laboratory, Max Delbrück Center for Molecular Medicine)

  • Mieke Dewerchin

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Myriam Baes

    (Laboratory of Cell Metabolism, KU Leuven, B-3000 Leuven, Belgium)

  • Katrien De Bock

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium
    Exercise Physiology Research Group, KU Leuven, B-3001 Leuven, Belgium)

  • Bart Ghesquière

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Sophia Y. Lunt

    (Michigan State University)

  • Sarah-Maria Fendt

    (Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

  • Peter Carmeliet

    (Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium
    Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium)

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.

Suggested Citation

  • 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 & L, 2015. "Fatty acid carbon is essential for dNTP synthesis in endothelial cells," Nature, Nature, vol. 520(7546), pages 192-197, April.
  • Handle: RePEc:nat:nature:v:520:y:2015:i:7546:d:10.1038_nature14362
    DOI: 10.1038/nature14362
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    Cited by:

    1. Balkrishna Chaube & Kathryn M. Citrin & Mahnaz Sahraei & Abhishek K. Singh & Diego Saenz Urturi & Wen Ding & Richard W. Pierce & Raaisa Raaisa & Rebecca Cardone & Richard Kibbey & Carlos Fernández-Her, 2023. "Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Ling Tao & Mahmoud A. Mohammad & Giorgio Milazzo & Myrthala Moreno-Smith & Tajhal D. Patel & Barry Zorman & Andrew Badachhape & Blanca E. Hernandez & Amber B. Wolf & Zihua Zeng & Jennifer H. Foster & , 2022. "MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Nieves Montenegro-Navarro & Claudia García-Báez & Melissa García-Caballero, 2023. "Molecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Kuei-Pin Chung & Chih-Ning Cheng & Yi-Jung Chen & Chia-Lang Hsu & Yen-Lin Huang & Min-Shu Hsieh & Han-Chun Kuo & Ya-Ting Lin & Yi-Hsiu Juan & Kiichi Nakahira & Yen-Fu Chen & Wei-Lun Liu & Sheng-Yuan R, 2024. "Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    5. Vincent Geldhof & Laura P. M. H. Rooij & Liliana Sokol & Jacob Amersfoort & Maxim Schepper & Katerina Rohlenova & Griet Hoste & Adriaan Vanderstichele & Anne-Marie Delsupehe & Edoardo Isnaldi & Naima , 2022. "Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    6. Odeta Meçe & Diede Houbaert & Maria-Livia Sassano & Tania Durré & Hannelore Maes & Marco Schaaf & Sanket More & Maarten Ganne & Melissa García-Caballero & Mila Borri & Jelle Verhoeven & Madhur Agrawal, 2022. "Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. Anastasiya Strembitska & Gwenaël Labouèbe & Alexandre Picard & Xavier P. Berney & David Tarussio & Maxime Jan & Bernard Thorens, 2022. "Lipid biosynthesis enzyme Agpat5 in AgRP-neurons is required for insulin-induced hypoglycemia sensing and glucagon secretion," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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