Ahmed, I.;Rajaganapathi, L.;Rivero, S.;Wei, J.;Espinel, S.;Bruder, A.;Kendi, A.;Bruder-Nascimento, T.;Espinosa-Diez, C.;Gomez, D.

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 limits vascular injury-induced neointima formation and atherosclerotic lesion expansion. Conversely, CASC15 overexpression exacerbates injury-induced neointimal hyperplasia. However, CASC15 KO mice exhibit 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 pro-proliferative function is mediated through its interaction with RNA-binding proteins, including Nucleolin, and by regulating 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 as a potential therapeutic target in cardiovascular disease.