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 upon early activation of the Smad2/3-Slug signaling pathway. Antagonism of TGF-β signaling by TGF-β neutralizing antibody, shRNA-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 restenosis.

Endothelial fluid shear stress sensing in vascular health and disease

“…EndMT results in reduced expression of endothelial-specific molecules including VE-cadherin and PECAM-1, which mediate flow sensing and could prevent flow-dependent remodeling. This hypothesis is corroborated by the observation that vein graft stenosis following exposure to the arterial environment, with consequent failed venous graft adaptation and remodeling, is characterized by SMAD2/3-dependent EndMT (88).…”

Endothelial-to-mesenchymal transition drives atherosclerosis progression

“…Staining for SMAD2/3 demonstrated increased translocation of these proteins to nuclei of HUVECs exposed to OSS, but not LSS, a finding consistent with activation of TGF-β signaling by OSS ( Figure 1B). In addition, OSS, but not LSS, induced a significant increase in mRNA levels of the transcription factor TWIST1 ( Figure 1C), which has been reported to be involved with TGF-β signaling (11,15). In agreement with this activation of the EndMT program, there was an increase in expression of SMC markers (ACTA2, which encodes smooth muscle α-actin, and NOTCH3) ( Figure 1D) and mesenchymal markers (N-cadherin, fibronectin 1, and collagen 1A) ( Figure 1E).…”

“…Recent studies have documented a high incidence of endothelial-to-mesenchymal transition (EndMT) in a number of pathological conditions associated with inflammation, such as myocardial infarction (6), cerebral cavernous malformations (7), portal hypertension (8), pulmonary hypertension (9), and vascular graft failure (10,11) among others. EndMT is characterized by a change in phenotype of normal endothelial cells (ECs) that assume the shape and properties of mesenchymal cells (fibroblasts, smooth muscle cells [SMCs]), including enhanced proliferation and migration; secretion of extracellular matrix proteins, such as fibronectin and collagen; and expression of various leukocyte adhesion molecules.…”

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

“…At a molecular level, transforming growth factor (TGF)-β has been implicated in the induction of EndMT [17,18], with a reduction in TGF-β signalling being associated with reduced neo-intima formation and decreased contribution of endothelial-derived cells to the neo-intima in vivo [17]. Recently, HOPPER et al [11] have provided insights into the mechanism by which TGF-β can induce EndMT.…”