miRNA-22 is a Novel Mediator of Vascular Smooth Muscle Cell Phenotypic Modulation and Neointima Formation
Background—MicroRNA-22 (miR-22) has recently been reported to play a regulatory role during vascular smooth muscle cell (VSMC) differentiation from stem cells, but little is known about its target genes and related pathways in mature VSMC phenotypic modulation or its clinical implication in neointima formation following vascular injury.
Methods—We applied wire-injury mouse model as well as local delivery of AgomiR-22 or miR-22 inhibitor to explore the therapeutic potential of miR-22 in vascular diseases. Furthermore, normal and diseased human femoral arteries were harvested and various in vivo, ex vivo, and in vitro models of VSMC phenotype switching were conducted to examine miR-22 expression during VSMC phenotype switching.
Results—Expression of miR-22 was closely regulated during VSMC phenotypic modulation. miR-22 over-expression significantly increased expression of VSMC marker genes and inhibited VSMC proliferation and migration, whilst the opposite effect was observed when endogenous miR-22 was knocked down. As expected, two previously reported miR-22 target genes, methyl-CpG binding protein 2 (MECP2) and histone deacetylase 4 (HDAC4), exhibited a regulatory role in VSMC phenotypic modulation. A transcriptional regulator and oncoprotein, Ecotropic Virus Integration Site 1 Protein Homolog (EVI1), has been identified as a novel miR-22 target gene in VSMC phenotypic modulation. Of note, overexpression of miR-22 in the injured vessels significantly reduced the expression of its target genes; decreased VSMC proliferation, and inhibited neointima formation in wire-injured femoral arteries, whilst the opposite effect was observed with local application of a miR-22 inhibitor to injured arteries. We next examined the clinical relevance of miR-22 expression and its target genes in human femoral arteries. We found that miR-22 expression was significantly reduced, while MECP2 and EVI1 expression levels were dramatically increased, in diseased compared to healthy femoral human arteries. This inverse relationship between miR-22 and MECP2 and/or EVI1 was evident in both healthy and diseased human femoral arteries.
Conclusions—Our data demonstrates that miR-22 and EVI1 are novel regulators of VSMC function specifically during neointima hyperplasia, offering a novel therapeutic opportunity for treating vascular diseases.
- VSMC phenotype switching
- vascular smooth muscle
- neointimal hyperplasia
- Received February 8, 2017.
- Revision received November 9, 2017.
- Accepted December 4, 2017.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.