TGF-β Signaling Mediates Endothelial-to-Mesenchymal Transition (EndMT) During Vein Graft Remodeling

In vivo endothelial cell fate mapping demonstrates that TGF-β signaling is a central pathway regulating the endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Negative Remodeling In coronary bypass surgery, veins are grafted to arteries, in hopes of generating a functional vessel. Although a routine procedure, grafting can result in a negative remodeling process—with a poorly understood underlying mechanism. Here, Cooley and colleagues linked vein graft stenosis (blood vessel narrowing) and negative remodeling to a process called the endothelial-to-mesenchymal transition (EndMT). Although well known during development, the presence of EndMT in the vasculature is less documented and therefore represents a possible new target in preventing graft failure. The authors tracked endothelial cells in mice using yellow fluorescent protein (YFP), and saw that these cells lining the vessel walls contributed to arterial thickening (neointima formation) after vein grafting by first converting to mesenchymal cells. EndMT occurred via transforming growth factor–β (TGF-β) signaling, specifically through intermediates Smad2/3 and Slug. Knowing the pathway at play is important for translation to the clinic because therapeutics can be designed to target these signaling molecules. Indeed, the authors found that blocking TGF-β with an antibody or knocking down Smad2 in vivo in mice prevented EndMT. The mesenchymal transition was also noted in failed vein grafts taken from patients, suggesting that EndMT is also present in humans and contributes to graft failure and restenosis. More testing is required in human samples to confirm the mouse data, but EndMT appears to be a viable target for improving graft outcomes after surgery in patients. 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.