Abstract
Mechanisms controlling vascular smooth muscle cell (VSMC) plasticity and renewal still remain to be elucidated completely. A class of small RNAs called microRNAs (miRs) regulate gene expression at the post-transcriptional level. Here, we show a critical role of the miR-143/145 cluster in SMC differentiation and vascular pathogenesis, also through the generation of a mouse model of miR-143 and -145 knockout (KO). We determined that the expression of miR-143 and -145 is decreased in acute and chronic vascular stress (transverse aortic constriction and in aortas of the ApoE KO mouse). In human aortic aneurysms, the expression of miR-143 and -145 was significantly decreased compared with control aortas. In addition, overexpression of miR-143 and -145 decreased neointimal formation in a rat model of acute vascular injury. An in-depth analysis of the miR-143/145 KO mouse model showed that this miR cluster is expressed mostly in the SMC compartment, both during development and postnatally, in vessels and SMC-containing organs. Loss of miR-143 and miR-145 expression induces structural modifications of the aorta, because of an incomplete differentiation of VSMCs. In conclusion, our results show that the miR-143/145 gene cluster has a critical role during SMC differentiation and strongly suggest its involvement in the reversion of the VSMC differentiation phenotype that occurs during vascular disease.
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Abbreviations
- VSMC:
-
vascular smooth muscle cell
- miRs:
-
microRNAs
- UTR:
-
untranslated region
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Acknowledgements
This work was supported by EUGeneHeart (LSHM-CT-2005-018833), Italian Ministry of Education and Fondation LeDucq grants to GC. The SAC laboratory is supported by the National Cancer Institute and the Mathers Foundation. We are grateful to Dr. Costanza Emanueli, Dr. Jason Johnson, Dr. Brunella Cristofaro and Dr. Saadeh Suleiman, Bristol University (UK) for the donation of the ApoE KO aortas and to Nancy D Dalton and Yusu Gu, University of California San Diego for technical support.
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Elia, L., Quintavalle, M., Zhang, J. et al. The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease. Cell Death Differ 16, 1590–1598 (2009). https://doi.org/10.1038/cdd.2009.153
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DOI: https://doi.org/10.1038/cdd.2009.153
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