title: TGF-β signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling.
abstract: Veins grafted into an arterial environment undergo a complex vascular remodeling process. Pathologic vascular remodeling often results in stenosed or occluded conduit grafts. Understanding this complex process is important for improving the outcome of patients with coronary and peripheral artery disease undergoing surgical revascularization. Using in vivo murine cell lineage-tracing models, we show that endothelial-derived cells contribute to neointimal formation through endothelial-to-mesenchymal transition (EndMT), which is dependent on early activation of the Smad2/3-Slug signaling pathway. Antagonism of transforming growth factor-β (TGF-β) signaling by TGF-β neutralizing antibody, short hairpin RNA-mediated Smad3 or Smad2 knockdown, Smad3 haploinsufficiency, or endothelial cell-specific Smad2 deletion resulted in decreased EndMT and less neointimal formation compared to controls. Histological examination of postmortem human vein graft tissue corroborated the changes observed in our mouse vein graft model, suggesting that EndMT is operative during human vein graft remodeling. These data establish that EndMT is an important mechanism underlying neointimal formation in interpositional vein grafts, and identifies the TGF-β-Smad2/3-Slug signaling pathway as a potential therapeutic target to prevent clinical vein graft stenosis.
authors.affiliation: Department of Orthopaedic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Cooley
authors.affiliation: National Institutes of Health-University of the Philippines College of Medicine, Ermita, Manila.|Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Nevado
authors.affiliation: William Harvey Research Institute, Barts and the London NHS Trust, London, EC1M 6BQ, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Mellad
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: St Hilaire
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Negro
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Guibin
authors.initials: G
authors.lastname: Chen
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: San
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Avram D
authors.initials: AD
authors.lastname: Walts
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Schwartzbeck
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Brandi
authors.initials: B
authors.lastname: Taylor
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Jan D
authors.initials: JD
authors.lastname: Lanzer
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.|William Harvey Research Institute, Barts and the London NHS Trust, London, EC1M 6BQ, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wragg
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.|Cardiovascular Department, Faculty of Medicine, Cairo University, Cairo 11559, Egypt.
authors.forename: Abdalla
authors.initials: A
authors.lastname: Elagha
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Leilani E
authors.initials: LE
authors.lastname: Beltran
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.|Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, Scotland, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Berry
authors.affiliation: Interfaculty Institute of Biochemistry, Universität Tübingen, 72074 Tübingen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
authors.affiliation: CVPath Institute, Inc., Gaithersburg, Maryland, 20878, USA.
authors.forename: Renu
authors.initials: R
authors.lastname: Virmani
authors.affiliation: CVPath Institute, Inc., Gaithersburg, Maryland, 20878, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Ladich
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.|The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Kovacic
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
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D019070:Cell Lineage / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D058426:Neointima / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014680:Veins / Q000187:drug effects / Q000254:growth & development* / Q000637:transplantation*
chemical_list: D057134:Antibodies, Neutralizing; C000604407:SNAI1 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta