Abstract
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.
Highlights
Coronary artery bypass grafting (CABG) is one of the most successful procedures for treating patients with coronary artery disease (CAD), and has been recommended as the gold standard for patients with multiple-vessel disease [1,2] and/or left main CAD regardless of the patient’s SYNTAX score [3,4,5], long-term survival rates in these patients are still poor and strongly limited by the development of graft vasculopathy or failure due to neointimal lesion formation
Human umbilical vein endothelial cells (HUVECs) treated with these two cytokines gradually underwent a clear morphological transition, adopting a more smooth muscle cell (SMC) or mesenchymal appearance over the 8-day treatment
Coincident with this morphological transition, HUVECs treated with transforming growth factor-β1 (TGFβ1)/TNFα displayed a significantly decreased expression of endothelial cell (EC) markers (PECAM1, CDH5, NOS3, VWF, and KDR), but a dramatically increased expression of mesenchymal/SMC markers (SMαA/ ACTA2, SM22α/TAGLN, SMTN, CDH2, DDR2, and FSP1/S100A4) and a host of endothelial– mesenchymal transition (EndoMT)-associated regulators (SNAI1, SNAI2, TWIST1, and TWIST2)
Summary
Coronary artery bypass grafting (CABG) is one of the most successful procedures for treating patients with coronary artery disease (CAD), and has been recommended as the gold standard for patients with multiple-vessel disease [1,2] and/or left main CAD regardless of the patient’s SYNTAX score (low, intermediate or high) [3,4,5], long-term survival rates in these patients are still poor and strongly limited by the development of graft vasculopathy or failure due to neointimal lesion formation. The origin of neointimal cells remains controversial, with increasing evidence pinpointing a contribution of medial SMCs, stem/progenitor cells [7,8], and endothelial– mesenchymal transition (EndoMT) [9,10,11,12,13]. EndoMT is a transition process characterized by loss of cell–cell adhesions and changes in cell polarity, with reduced expression of endothelial cell (EC) markers but increased expression of mesenchymal cell (or SMC-like) markers. The resultant cells acquire myofibroblast-like characteristics with contractile function, enhanced migratory and proliferative phenotype, and increased extracellular matrix production. They lose EC functional characteristics with an impaired antithrombogenicity and angiogenesis [11,14,15]
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