Abstract
The phenotypic switch of vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of various vascular diseases, such as atherosclerosis and post-angioplasty restenosis. Small non-coding microRNAs (miRNAs) have emerged as critical modulators of VSMC function. In the present study, miR-26a was significantly increased in cultured VSMCs stimulated by platelet-derived growth factor-BB (PDGF-BB) and in arteries with neointimal lesion formation. Moreover, we demonstrated that miR-26a regulates the expression of VSMC differentiation marker genes such as α-smooth muscle actin (α-SMA), calponin and smooth muscle myosin heavy chain (SM-MHC) in PDGF-BB-treated VSMCs. We further confirmed that the regulatory effect of miR-26a during the phenotypic transition occurs through its target gene Smad1, which is a critical mediator of the pro-contractile signal transmitted by bone morphogenetic protein (BMP) and transforming growth factor-beta (TGF-β). This discovery proposed a new channel for communication between PDGF and the BMP/TGF-β family. We concluded that miR-26a is an important regulator in the PDGF-BB-mediated VSMC phenotypic transition by targeting Smad1. Interventions aimed at miR-26a may be promising in treating numerous proliferative vascular disorders.
Highlights
Vascular smooth muscle cells (VSMCs) exhibit extensive plasticity and can undergo phenotypic changes from a quiescent contractile state to a proliferative synthetic state in response to various cellular stimuli [1, 2]
We further confirmed that the regulatory effect of miR-26a during the phenotypic transition occurs through its target gene Smad1, which is a critical mediator of the pro-contractile signal transmitted by bone morphogenetic protein (BMP) and transforming growth factor-beta (TGF-β)
We previously demonstrated that platelet-derived growth factor-BB (PDGF-BB) is upregulated in vascular smooth muscle cells (VSMCs) in the balloon-injury model of rat [22], thereby confirming its key role in modulating the VSMC proliferation during neointimal hyperplasia
Summary
Vascular smooth muscle cells (VSMCs) exhibit extensive plasticity and can undergo phenotypic changes from a quiescent contractile state to a proliferative synthetic state in response to various cellular stimuli [1, 2]. The aberrant transition of VSMCs phenotype plays a pivotal role in the pathogenesis of a variety of cardiovascular diseases, such as atherosclerosis, hypertension and postangioplasty restenosis [3, 4]. The synthetic VSMC phenotype is marked by increased migration, proliferation and production of extracellular matrix components as well as decreased expression of dedifferentiation markers, including α-smooth muscle actin (α-SMA), calponin and smooth muscle myosin heavy chains (SMMHC) [1, 2]. The VSMC phenotype is modulated by a variety of environmental cues, including growth factors, cell-cell contact, extracellular matrix components, and neuronal input [2, 4]. Understanding the molecular mechanism underlying PDGF-BB-induced VSMC phenotype modulation is a priority in this field
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