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

Vascular smooth muscle cell (SMC) growth, whether hyperplastic or hypertrophic, is a central determinant of vascular remodeling in cardiovascular disease, yet the molecular regulators that direct SMC toward a specific growth fate remain poorly understood. 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. However, CASC15 KO mice exhibited spontaneous medial hypertrophy and vascular hypercontractility. Mechanistically, loss of S-CASC15 expression causes mitotic defects, followed by arrest in the G1 phase of hypertrophic and polyploid cells. We found that S-CASC15 interacts with RNA-binding proteins, including Nucleolin, to control RNA processing, splicing, and stability. Specifically, CASC15 regulates the stability of cell cycle checkpoint gene transcripts, thereby ensuring mitotic fidelity. Together, these findings establish CASC15 as a pivotal molecular switch governing the balance between hyperplastic and hypertrophic vascular remodeling and a potential therapeutic target in cardiovascular disease.