title: Meox2/Tcf15 heterodimers program the heart capillary endothelium for cardiac fatty acid uptake.
abstract: BACKGROUND
  Microvascular endothelium in different organs is specialized to fulfill the particular needs of parenchymal cells. However, specific information about heart capillary endothelial cells (ECs) is lacking.
  
  
  RESULTS
  Using microarray profiling on freshly isolated ECs from heart, brain, and liver, we revealed a genetic signature for microvascular heart ECs and identified Meox2/Tcf15 heterodimers as novel transcriptional determinants. This signature was largely shared with skeletal muscle and adipose tissue endothelium and was enriched in genes encoding fatty acid (FA) transport-related proteins. Using gain- and loss-of-function approaches, we showed that Meox2/Tcf15 mediate FA uptake in heart ECs, in part, by driving endothelial CD36 and lipoprotein lipase expression and facilitate FA transport across heart ECs. Combined Meox2 and Tcf15 haplodeficiency impaired FA uptake in heart ECs and reduced FA transfer to cardiomyocytes. In the long term, this combined haplodeficiency resulted in impaired cardiac contractility.
  
  
  CONCLUSIONS
  Our findings highlight a regulatory role for ECs in FA transfer to the heart parenchyma and unveil 2 of its intrinsic regulators. Our insights could be used to develop new strategies based on endothelial Meox2/Tcf15 targeting to modulate FA transfer to the heart and remedy cardiac dysfunction resulting from altered energy substrate usage.
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Giulia
authors.initials: G
authors.lastname: Coppiello
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Collantes
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: María Salomé
authors.initials: MS
authors.lastname: Sirerol-Piquer
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Vandenwijngaert
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schoors
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Melissa
authors.initials: M
authors.lastname: Swinnen
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Ine
authors.initials: I
authors.lastname: Vandersmissen
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Herijgers
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Baki
authors.initials: B
authors.lastname: Topal
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Johannes
authors.initials: J
authors.lastname: van Loon
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Goffin
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Felipe
authors.initials: F
authors.lastname: Prósper
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: García-Verdugo
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Janssens
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Iván
authors.initials: I
authors.lastname: Peñuelas
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
authors.forename: Xabier L
authors.initials: XL
authors.lastname: Aranguren
authors.affiliation: From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium. aernout.luttun@med.kuleuven.be.
authors.forename: Aernout
authors.initials: A
authors.lastname: Luttun
mesh_terms: D000273:Adipose Tissue / Q000098:blood supply; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018955:CD36 Antigens / Q000096:biosynthesis / Q000235:genetics; D002303:Cardiac Output, Low / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology; D042783:Endothelial Cells / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008071:Lipoprotein Lipase / Q000096:biosynthesis / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D025941:Protein Interaction Mapping; D034741:RNA, Small Interfering / Q000494:pharmacology; D046888:Tissue Array Analysis; D059467:Transcriptome
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018955:CD36 Antigens; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D005947:Glucose; D018398:Homeodomain Proteins; D008071:Lipoprotein Lipase; D008079:Lipoproteins, VLDL; D034741:RNA, Small Interfering; C484194:Meox2 protein, mouse; C093234:Tcf15 protein, mouse; C548261:LPL protein, human
keywords: endothelium; fatty acids; heart; metabolism; transcription factors