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Sci Transl Med. 2014 Mar 12;6(227):227ra34. doi: 10.1126/scitranslmed.3006927.

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

Author information

1
Department of Orthopaedic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA.
2
National Institutes of Health-University of the Philippines College of Medicine, Ermita, Manila.
3
Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
4
William Harvey Research Institute, Barts and the London NHS Trust, London, EC1M 6BQ, UK.
5
Cardiovascular Department, Faculty of Medicine, Cairo University, Cairo 11559, Egypt.
6
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, Scotland, UK.
7
Interfaculty Institute of Biochemistry, Universität Tübingen, 72074 Tübingen, Germany.
8
CVPath Institute, Inc., Gaithersburg, Maryland, 20878, USA.
9
The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
#
Contributed equally

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.

PMID:
24622514
PMCID:
PMC4181409
DOI:
10.1126/scitranslmed.3006927
[Indexed for MEDLINE]
Free PMC Article
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