Abstract
Phenotypic modulation of smooth muscle cells (SMCs) plays a key role in vascular disease, including atherosclerosis. Several transcription factors have been suggested to regulate phenotypic modulation of SMCs but the decisive mechanisms remain unknown. Recent reports suggest that specific microRNAs (miRNAs) are involved in SMC differentiation and vascular disease but the global role of miRNAs in postnatal vascular SMC has not been elucidated. Thus, the objective of this study was to identify the role of Dicer-dependent miRNAs for blood pressure regulation and vascular SMC contractile function and differentiation in vivo. Tamoxifen-inducible and SMC specific deletion of Dicer was achieved by Cre-Lox recombination. Deletion of Dicer resulted in a global loss of miRNAs in aortic SMC. Furthermore, Dicer-deficient mice exhibited a dramatic reduction in blood pressure due to significant loss of vascular contractile function and SMC contractile differentiation as well as vascular remodeling. Several of these results are consistent with our previous observations in SM-Dicer deficient embryos. Therefore, miRNAs are essential for maintaining blood pressure and contractile function in resistance vessels. Although the phenotype of miR-143/145 deficient mice resembles the loss of Dicer, the phenotypes of SM-Dicer KO mice were far more severe suggesting that additional miRNAs are involved in maintaining postnatal SMC differentiation.
Highlights
In vivo, medial vascular smooth muscle cells (VSMCs) are normally quiescent and programmed for contraction but under certain conditions these cells undergo phenotypic modulation which may result in increased proliferation and/or migration from the media [1]
To confirm loss of Dicer and miRNAs in VSMC, Dicer mRNA and several miRNAs were analyzed by RT-Quantitative real time PCR (qPCR) in control and SM-Dicer KO aorta
We have previously shown that cultured aortic VSMC isolated from SM-Dicer KO mice 10 weeks post-tamoxifen have a .80% knock down of Dicer [27]
Summary
Medial vascular smooth muscle cells (VSMCs) are normally quiescent and programmed for contraction but under certain conditions these cells undergo phenotypic modulation which may result in increased proliferation and/or migration from the media [1]. Several transcription factors, including serum response factor (SRF), myocardin, myocardin related transcription factors (MRTFs) and members of the Kruppel-like zinc finger family (KLF) have been suggested to act as molecular switches regulating VSMC differentiation [2,3]. MicroRNAs (miRNAs), which are short (,22 nt) noncoding RNAs have been suggested to regulate mRNA expression levels and translational efficiency and play a fundamental role in a number of human disease states, including vascular disease [4,5]. Specific miRNAs have been shown to regulate VSMC phenotypic modulation and/or control VSMC fate and differentiation [6,7,8,9,10,11,12]. Studies on miR-143/145 KO mice later revealed that these miRNAs are important but not essential for VSMC development in vivo [13,14,15]
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