Long noncoding RNA <i>NEAT1</i> (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells.

Abstract

In response to vascular injury, vascular smooth muscle cells (VSMCs) may switch from a contractile to a proliferative phenotype thereby contributing to neointima formation. Previous studies showed that the long noncoding RNA (lncRNA) <i>NEAT1</i> is critical for paraspeckle formation and tumorigenesis by promoting cell proliferation and migration. However, the role of <i>NEAT1</i> in VSMC phenotypic modulation is unknown. Herein we showed that <i>NEAT1</i> expression was induced in VSMCs during phenotypic switching in vivo and in vitro. Silencing <i>NEAT1</i> in VSMCs resulted in enhanced expression of SM-specific genes while attenuating VSMC proliferation and migration. Conversely, overexpression of <i>NEAT1</i> in VSMCs had opposite effects. These in vitro findings were further supported by in vivo studies in which <i>NEAT1</i> knockout mice exhibited significantly decreased neointima formation following vascular injury, due to attenuated VSMC proliferation. Mechanistic studies demonstrated that <i>NEAT1</i> sequesters the key chromatin modifier WDR5 (WD Repeat Domain 5) from SM-specific gene loci, thereby initiating an epigenetic "off" state, resulting in down-regulation of SM-specific gene expression. Taken together, we demonstrated an unexpected role of the lncRNA <i>NEAT1</i> in regulating phenotypic switching by repressing SM-contractile gene expression through an epigenetic regulatory mechanism. Our data suggest that <i>NEAT1</i> is a therapeutic target for treating occlusive vascular diseases.