The Source of Neointimal Cells in Vein Grafts: Does the Origin Matter?

Rienstra, Heleen; Zeebregts, Clark J.; Hillebrands, Jan-Luuk

doi:10.2353/ajpath.2008.071219

Cited by 2 publications

(2 citation statements)

References 25 publications

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“…The major cause for vascular graft loss/failure after CABG is accelerated coronary allograft arteriosclerosis, characterized by neointimal hyperplasia consisting mainly of SMC-/myofibroblast-like cells. However, the cellular origins of these neointimal cells are still undergoing extensive debate [39,40]. EndoMT has recently been suggested as an important driver of neointima formation in a murine transplant arteriopathy model and in rejecting human transplant lesions [6].…”

Section: Discussionmentioning

confidence: 99%

miRNA‐200c‐3p promotes endothelial to mesenchymal transition and neointimal hyperplasia in artery bypass grafts

Chen

Zhang

Chen

et al. 2020

The Journal of Pathology

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Increasing evidence has suggested a critical role for endothelial‐to‐mesenchymal transition (EndoMT) in a variety of pathological conditions. MicroRNA‐200c‐3p (miR‐200c‐3p) has been implicated in epithelial‐to‐mesenchymal transition. However, the functional role of miR‐200c‐3p in EndoMT and neointimal hyperplasia in artery bypass grafts remains largely unknown. Here we demonstrated a critical role for miR‐200c‐3p in EndoMT. Proteomics and luciferase activity assays revealed that fermitin family member 2 (FERM2) is the functional target of miR‐200c‐3p during EndoMT. FERMT2 gene inactivation recapitulates the effect of miR‐200c‐3p overexpression on EndoMT, and the inhibitory effect of miR‐200c‐3p inhibition on EndoMT was reversed by FERMT2 knockdown. Further mechanistic studies revealed that FERM2 suppresses smooth muscle gene expression by preventing serum response factor nuclear translocation and preventing endothelial mRNA decay by interacting with Y‐box binding protein 1. In a model of aortic grafting using endothelial lineage tracing, we observed that miR‐200c‐3p expression was dramatically up‐regulated, and that EndoMT contributed to neointimal hyperplasia in grafted arteries. MiR‐200c‐3p inhibition in grafted arteries significantly up‐regulated FERM2 gene expression, thereby preventing EndoMT and reducing neointimal formation. Importantly, we found a high level of EndoMT in human femoral arteries with atherosclerotic lesions, and that miR‐200c‐3p expression was significantly increased, while FERMT2 expression levels were dramatically decreased in diseased human arteries. Collectively, we have documented an unexpected role for miR‐200c‐3p in EndoMT and neointimal hyperplasia in grafted arteries. Our findings offer a novel therapeutic opportunity for treating vascular diseases by specifically targeting the miR‐200c‐3p/FERM2 regulatory axis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

miRNA‐200c‐3p promotes endothelial to mesenchymal transition and neointimal hyperplasia in artery bypass grafts

Chen

Zhang

Chen

et al. 2020

The Journal of Pathology

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“…The use of autologous human saphenous vein (HSV) is the most common surgical intervention for the bypass of occluded multivessel coronary artery disease (CAD), despite the use of alternative sources of graft such as the internal mammary artery. Although successful in reducing overall rates of mortality and morbidity in CAD patients, 50% of long-term vein grafts become occluded due to intimal hyperplasia [ 1 ]. The pathophysiology of vein graft disease is defined by a cascade of events leading to neointimal formation and graft occlusion.…”

Section: Introductionmentioning

confidence: 99%

G-Protein-Coupled Receptor 35 Mediates Human Saphenous Vein Vascular Smooth Muscle Cell Migration and Endothelial Cell Proliferation

McCallum¹,

Mackenzie

Divorty

et al. 2015

J Vasc Res

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Vascular smooth muscle cell (VSMC) migration and proliferation is central to neointima formation in vein graft failure following coronary artery bypass. However, there are currently no pharmacological interventions that prevent vein graft failure through intimal occlusion. It is hence a therapeutic target. Here, we investigated the contribution of GPR35 to human VSMC and endothelial cell (EC) migration, using a scratch-wound assay, and also the contribution to proliferation, using MTS and BrdU assays, in in vitro models using recently characterized human GPR35 ortholog-selective small-molecule agonists and antagonists. Real-time PCR studies showed GPR35 to be robustly expressed in human VSMCs and ECs. Stimulation of GPR35, with either the human-selective agonist pamoic acid or the reference agonist zaprinast, promoted VSMC migration in the scratch-wound assay. These effects were blocked by coincubation with either of the human GPR35-specific antagonists, CID-2745687 or ML-145. These GPR35-mediated effects were produced by inducing alterations in the actin cytoskeleton via the Rho A/Rho kinase signaling axis. Additionally, the agonist ligands stimulated a proliferative response in ECs. These studies highlight the potential that small molecules that stimulate or block GPR35 activity can modulate vascular proliferation and migration. These data propose GPR35 as a translational therapeutic target in vascular remodeling.

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The Source of Neointimal Cells in Vein Grafts: Does the Origin Matter?

Cited by 2 publications

References 25 publications

miRNA‐200c‐3p promotes endothelial to mesenchymal transition and neointimal hyperplasia in artery bypass grafts

miRNA‐200c‐3p promotes endothelial to mesenchymal transition and neointimal hyperplasia in artery bypass grafts

G-Protein-Coupled Receptor 35 Mediates Human Saphenous Vein Vascular Smooth Muscle Cell Migration and Endothelial Cell Proliferation

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