title: Fatty acid carbon is essential for dNTP synthesis in endothelial cells.
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.
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schoors
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bruning
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Rindert
authors.initials: R
authors.lastname: Missiaen
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Karla Cs
authors.initials: KC
authors.lastname: Queiroz
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Gitte
authors.initials: G
authors.lastname: Borgers
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Elia
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Zecchin
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Cantelmo
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Christen
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Jermaine
authors.initials: J
authors.lastname: Goveia
authors.affiliation: Center for Molecular & Vascular Biology, KU Leuven; Division of Clinical Cardiology, UZ Leuven, B-3000, Belgium.
authors.forename: Ward
authors.initials: W
authors.lastname: Heggermont
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Lucica
authors.initials: L
authors.lastname: Goddé
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vinckier
authors.affiliation: Laboratory of Lipid biochemistry and protein interactions, University of Leuven, B-3000, Leuven, Belgium.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Van Veldhoven
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Eelen
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Schoonjans
authors.affiliation: Vascular Patterning Laboratory, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.|Integrative Vascular Biology Laboratory, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.affiliation: Laboratory of Cell Metabolism, Department of pharmaceutical and pharmacological sciences, University of Leuven, Leuven, B-3000,Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Baes
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.|Exercise Physiology Research Group, Department of Kinesiology, University of Leuven, Leuven, B-3001, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: De Bock
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Ghesquière
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Lunt
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Sarah-Maria
authors.initials: SM
authors.lastname: Fendt
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.|Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D019342:Acetic Acid / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002244:Carbon / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002952:Citric Acid Cycle; D004247:DNA / Q000096:biosynthesis; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005227:Fatty Acids / Q000737:chemistry* / Q000378:metabolism*; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009711:Nucleotides / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D012178:Retinopathy of Prematurity / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D005227:Fatty Acids; D009711:Nucleotides; D002244:Carbon; D000255:Adenosine Triphosphate; D004247:DNA; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose; D019342:Acetic Acid
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