TGF-β signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling

Brian C Cooley; Jose Nevado; Jason Mellad; Dan Yang; Cynthia St Hilaire; Alejandra Negro; Fang Fang; Guibin Chen; Hong San; Avram D Walts; Robin L Schwartzbeck; Brandi Taylor; Jan D Lanzer; Andrew Wragg; Abdalla Elagha; Leilani E Beltran; Colin Berry; Robert Feil; Renu Virmani; Elena Ladich; Jason C Kovacic; Manfred Boehm

doi:10.1126/scitranslmed.3006927

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TGF-β signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling

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TGF-β signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling

Brian C Cooley, Jose Nevado, Jason Mellad, Dan Yang, Cynthia St Hilaire, Alejandra Negro, Fang Fang, Guibin Chen, Hong San, Avram D Walts, …

Science translational medicine, Vol.6(227), pp.227ra34-227ra34

12/03/2014

DOI: https://doi.org/10.1126/scitranslmed.3006927

PMID: 24622514

Résumé

Animals

Antibodies, Neutralizing - pharmacology

Cell Lineage - drug effects

Cell Transdifferentiation - drug effects

Endothelial Cells - cytology

Endothelial Cells - drug effects

Endothelial Cells - metabolism

Gene Knockdown Techniques

Humans

Mesoderm - cytology

Mesoderm - drug effects

Mesoderm - metabolism

Mice

Neointima - metabolism

Signal Transduction - drug effects

Smad2 Protein - metabolism

Smad3 Protein - metabolism

Snail Family Transcription Factors

Transcription Factors - metabolism

Transforming Growth Factor beta - metabolism

Veins - drug effects

Veins - growth & development

Veins - transplantation

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.

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Titre: TGF-β signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling
Créateurs - sans rôle: Brian C Cooley - Department of Orthopaedic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA
Jose Nevado - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Jason Mellad - William Harvey Research Institute, Barts and the London NHS Trust, London, EC1M 6BQ, UK
Dan Yang - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Cynthia St Hilaire - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Alejandra Negro - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Fang Fang - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Guibin Chen - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Hong San - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Avram D Walts - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Robin L Schwartzbeck - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Brandi Taylor - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Jan D Lanzer - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Andrew Wragg - William Harvey Research Institute, Barts and the London NHS Trust, London, EC1M 6BQ, UK
Abdalla Elagha - Cardiovascular Department, Faculty of Medicine, Cairo University, Cairo 11559, Egypt
Leilani E Beltran - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Colin Berry - Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, Scotland, UK
Robert Feil - Interfaculty Institute of Biochemistry, Universität Tübingen, 72074 Tübingen, Germany
Renu Virmani - CVPath Institute
Elena Ladich - CVPath Institute, Inc., Gaithersburg, Maryland, 20878, USA
Jason C Kovacic - The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
Manfred Boehm - Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
Détails de publication: Science translational medicine, Vol.6(227), pp.227ra34-227ra34
Note de subvention: K08HL111330 / NHLBI NIH HHS ZIA HL006078 / Intramural NIH HHS K08 HL111330 / NHLBI NIH HHS
Identifiants: 99153938309311
Unité académique: Institut de Génétique Moléculaire de Montpellier - IGMM
Langue: English
Type de ressource: Journal article