CASC15 dictates vascular smooth muscle cell growth fate and pathological vascular remodeling through post-transcription regulation of mitotic fidelity

Here, we identify the long non-coding RNA CASC15 as a critical regulator of SMC growth and vascular remodeling. CASC15 is enriched in the vasculature and SMC-rich tissues in humans and mice, and its locus harbors SNPs significantly associated with coronary artery disease and blood pressure.

We identify a novel SMC-selective CASC15 isoform (S-CASC15) whose expression level determines SMC growth fate: elevated S-CASC15 promotes proliferation, while its loss drives hypertrophy, polyploidization, and binucleation. In vivo depletion of CASC15 limited vascular injury-induced neointima formation and atherosclerotic lesion expansion. Conversely, CASC15 overexpression exacerbates injury-induced neointimal hyperplasia.