title: The role of fatty acid β-oxidation in lymphangiogenesis.
abstract: Lymphatic vessels are lined by lymphatic endothelial cells (LECs), and are critical for health. However, the role of metabolism in lymphatic development has not yet been elucidated. Here we report that in transgenic mouse models, LEC-specific loss of CPT1A, a rate-controlling enzyme in fatty acid β-oxidation, impairs lymphatic development. LECs use fatty acid β-oxidation to proliferate and for epigenetic regulation of lymphatic marker expression during LEC differentiation. Mechanistically, the transcription factor PROX1 upregulates CPT1A expression, which increases acetyl coenzyme A production dependent on fatty acid β-oxidation. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes. PROX1-p300 interaction facilitates preferential histone acetylation at PROX1-target genes. Through this metabolism-dependent mechanism, PROX1 mediates epigenetic changes that promote lymphangiogenesis. Notably, blockade of CPT1 enzymes inhibits injury-induced lymphangiogenesis, and replenishing acetyl coenzyme A by supplementing acetate rescues this process in vivo.
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Wong
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Xingwu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Zecchin
authors.affiliation: Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Translational Genetics, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thienpont
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Ivo
authors.initials: I
authors.lastname: Cornelissen
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kalucka
authors.affiliation: Laboratory of Biology of Tumor and Development, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège B-4000, Belgium.
authors.forename: Melissa
authors.initials: M
authors.lastname: García-Caballero
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Rindert
authors.initials: R
authors.lastname: Missiaen
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Hongling
authors.initials: H
authors.lastname: Huang
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Brüning
authors.affiliation: Laboratory of Biology of Tumor and Development, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège B-4000, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vinckier
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Jermaine
authors.initials: J
authors.lastname: Goveia
authors.affiliation: Brain Research Institute, Faculty of Medicine and Science, University of Zurich, Zurich 8057, Switzerland.
authors.forename: Marlen
authors.initials: M
authors.lastname: Knobloch
authors.affiliation: Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Translational Genetics, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster 48161, Germany.
authors.forename: Cathrin
authors.initials: C
authors.lastname: Dierkes
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Chenyan
authors.initials: C
authors.lastname: Shi
authors.affiliation: Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster 48161, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Hägerling
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.|Metabolomics Core Facility, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Veronica
authors.initials: V
authors.lastname: Moral-Dardé
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wyns
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Martin
authors.initials: M
authors.lastname: Lippens
authors.affiliation: Brain Research Institute, Faculty of Medicine and Science, University of Zurich, Zurich 8057, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jessberger
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Vesalius Research Center, VIB, B-3000 Leuven, Belgium.|Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), B-3000 Leuven, Belgium.
authors.forename: Sarah-Maria
authors.initials: SM
authors.lastname: Fendt
authors.affiliation: Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven B-3000, Belgium.
authors.forename: Aernout
authors.initials: A
authors.lastname: Luttun
authors.affiliation: Laboratory of Biology of Tumor and Development, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège B-4000, Belgium.
authors.forename: Agnès
authors.initials: A
authors.lastname: Noel
authors.affiliation: Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster 48161, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Kiefer
authors.affiliation: Metabolomics Core Facility, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Ghesquière
authors.affiliation: Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of Biology, KU Leuven, Leuven B-3000, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Schoonjans
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Eelen
authors.affiliation: Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Translational Genetics, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic; D005227:Fatty Acids / Q000737:chemistry* / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects / Q000235:genetics; D042601:Lymphatic Vessels / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction / Q000187:drug effects; D014176:Protein Biosynthesis; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014469:Umbilical Arteries / Q000166:cytology; D015854:Up-Regulation; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D000085:Acetates; D005227:Fatty Acids; D006657:Histones; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D000105:Acetyl Coenzyme A; C558401:CPT1B protein, mouse; D002334:Carnitine O-Palmitoyltransferase