title: Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability.
abstract: Endothelial to mesenchymal transition (EndMT) plays a major role during development, and also contributes to several adult cardiovascular diseases. Importantly, mesenchymal cells including fibroblasts are prominent in atherosclerosis, with key functions including regulation of: inflammation, matrix and collagen production, and plaque structural integrity. However, little is known about the origins of atherosclerosis-associated fibroblasts. Here we show using endothelial-specific lineage-tracking that EndMT-derived fibroblast-like cells are common in atherosclerotic lesions, with EndMT-derived cells expressing a range of fibroblast-specific markers. In vitro modelling confirms that EndMT is driven by TGF-β signalling, oxidative stress and hypoxia; all hallmarks of atherosclerosis. 'Transitioning' cells are readily detected in human plaques co-expressing endothelial and fibroblast/mesenchymal proteins, indicative of EndMT. The extent of EndMT correlates with an unstable plaque phenotype, which appears driven by altered collagen-MMP production in EndMT-derived cells. We conclude that EndMT contributes to atherosclerotic patho-biology and is associated with complex plaques that may be related to clinical events.
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Solene M
authors.initials: SM
authors.lastname: Evrard
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Lecce
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Michelis
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Aya
authors.initials: A
authors.lastname: Nomura-Kitabayashi
authors.affiliation: Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Gaurav
authors.identifier: 0000-0003-1939-679X
authors.initials: G
authors.lastname: Pandey
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: K-Raman
authors.initials: KR
authors.lastname: Purushothaman
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: d'Escamard
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Li
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Lahouaria
authors.initials: L
authors.lastname: Hadri
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Fujitani
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Moreno
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Benard
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Pauline
authors.initials: P
authors.lastname: Rimmele
authors.affiliation: Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Ariella
authors.initials: A
authors.lastname: Cohain
authors.affiliation: Trialomics LLC, Seattle, Washington 98115, USA.
authors.forename: Brigham
authors.initials: B
authors.lastname: Mecham
authors.affiliation: Department of Pathology and Immunology, Washington University, St Louis, Missouri 63110, USA.
authors.forename: Gwendalyn J
authors.initials: GJ
authors.lastname: Randolph
authors.affiliation: Brigham and Women's Health Care, Boston, Massachusetts 02115, USA.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Nabel
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Hajjar
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Valentin
authors.initials: V
authors.lastname: Fuster
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Manfred
authors.initials: M
authors.lastname: Boehm
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Jason C
authors.identifier: 0000-0003-4555-769X
authors.initials: JC
authors.lastname: Kovacic
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D051379:Mice; D018384:Oxidative Stress; D010101:Oxygen Consumption; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016212:Transforming Growth Factor beta