Vascular smooth muscle cell phenotype switching in carotid atherosclerosis.

Carotid plaque instability contributes to large vessel ischemic stroke. Although vascular smooth muscle cells (VSMCs) affect atherosclerotic growth and instability, no treatments aimed at improving VSMC function are available. Large genetic studies investigating atherosclerosis and carotid disease in relation to the risk of stroke have implicated polymorphisms at the HDAC9 locus. The HDAC9 protein has been shown to affect the VSMC phenotype; however, how this might affect carotid disease is unknown. We conducted a pilot investigation using single nuclei RNA sequencing of human carotid tissue to identify cells expressing HDAC9 and specifically investigate the role of the HDAC9 in carotid atherosclerosis. We found that carotid VSMCs express HDAC9 and genes typically associated with immune characteristics. Using cellular assays, we have demonstrated that recruitment of macrophages can be modulated by HDAC9 expression. HDAC9 expression might affect carotid plaque stability and progression through its effects on the VSMC phenotype and recruitment of immune cells.