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Background: Vascular homeostasis is maintained by the differentiated phenotype of vascular smooth muscle cells (VSMCs). The landscape of protein coding genes comprising the transcriptome of differentiated VSMCs has been intensively investigated but many gaps remain including the emerging roles of noncoding genes. Methods: We reanalyzed large-scale, publicly available bulk and single-cell RNA sequencing datasets from multiple tissues and cell types to identify VSMC-enriched long noncoding RNAs. The in vivo expression pattern of a novel smooth muscle cell (SMC)–expressed long noncoding RNA,Carmn (cardiac mesoderm enhancer-associated noncoding RNA), was investigated using a novelCarmn green fluorescent protein knock-in reporter mouse model. Bioinformatics and quantitative real-time polymerase chain reaction analysis were used to assessCARMN expression changes during VSMC phenotypic modulation in human and murine vascular disease models. In vitro, functional assays were performed by knocking downCARMN with antisense oligonucleotides and overexpressingCarmn by adenovirus in human coronary artery SMCs. Carotid artery injury was performed in SMC-specificCarmn knockout mice to assess neointima formation and the therapeutic potential of reversingCARMN loss was tested in a rat carotid artery balloon injury model. The molecular mechanisms underlyingCARMN function were investigated using RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays.Results: We identifiedCARMN , which was initially annotated as the host gene of theMIR143/145 cluster and recently reported to play a role in cardiac differentiation, as a highly abundant and conserved, SMC-specific long noncoding RNA. Analysis of theCarmn GFP knock-in mouse model confirmed thatCarmn is transiently expressed in embryonic cardiomyocytes and thereafter becomes restricted to SMCs. We also found thatCarmn is transcribed independently ofMir143/145 .CARMN expression is dramatically decreased by vascular disease in humans and murine models and regulates the contractile phenotype of VSMCs in vitro. In vivo, SMC-specific deletion ofCarmn significantly exacerbated, whereas overexpression ofCarmn markedly attenuated, injury-induced neointima formation in mouse and rat, respectively. Mechanistically, we found thatCarmn physically binds to the key transcriptional cofactor myocardin, facilitating its activity and thereby maintaining the contractile phenotype of VSMCs.Conclusions: CARMN is an evolutionarily conserved SMC-specific long noncoding RNA with a previously unappreciated role in maintaining the contractile phenotype of VSMCs and is the first noncoding RNA discovered to interact with myocardin.

CARMN Is an Evolutionarily Conserved Smooth Muscle Cell–Specific LncRNA That Maintains Contractile Phenotype by Binding Myocardin