title: Mesenchymal-endothelial transition contributes to cardiac neovascularization.
abstract: Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial-cell-like phenotype after acute ischaemic cardiac injury. Fibroblast-derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reduces post-infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal-to-endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair.
authors.affiliation: Department of Cell Biology &Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Ubil
authors.affiliation: 1] Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Eli and Edythe Broad Institute of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California 90095, USA [4] Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, California 90095, USA [5] Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA [6] Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Jinzhu
authors.initials: J
authors.lastname: Duan
authors.affiliation: 1] Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Eli and Edythe Broad Institute of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California 90095, USA [4] Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, California 90095, USA [5] Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA [6] Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Indulekha C L
authors.initials: IC
authors.lastname: Pillai
authors.affiliation: 1] Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [4] Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rosa-Garrido
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bargiacchi
authors.affiliation: 1] Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Eli and Edythe Broad Institute of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California 90095, USA [4] Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, California 90095, USA [5] Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA [6] Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: 1] Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Eli and Edythe Broad Institute of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California 90095, USA [4] Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, California 90095, USA [5] Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA [6] Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Seta
authors.initials: S
authors.lastname: Stanbouly
authors.affiliation: 1] Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Eli and Edythe Broad Institute of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California 90095, USA [4] Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, California 90095, USA [5] Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA [6] Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Medicine, McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.affiliation: 1] Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Molecular Biology Institute, University of California, Los Angeles, California 90095, USA [4] Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [5] Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Vondriska
authors.affiliation: 1] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
authors.forename: Enrico
authors.initials: E
authors.lastname: Stefani
authors.affiliation: 1] Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Eli and Edythe Broad Institute of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California 90095, USA [4] Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, California 90095, USA [5] Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA [6] Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Deb
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation; D003331:Coronary Vessels / Q000166:cytology* / Q000254:growth & development*; D042783:Endothelial Cells / Q000166:cytology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D017202:Myocardial Ischemia / Q000473:pathology*; D018919:Neovascularization, Physiologic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53