SPARC is associated with vascular smooth muscle cell senescence and vascular remodeling in intracranial aneurysms

Abstract Background Intracranial aneurysms (IAs) affect approximately 3% of adults, and no pharmacological therapy is available to stabilize the aneurysm wall. Vascular smooth muscle cell (VSMC) senescence may contribute to IA formation, but its molecular regulators remain unclear. Secreted protein acidic and rich in cysteine (SPARC), a matricellular protein of the FRIDMAN_SENESCENCE_UP gene set, regulates cell–matrix interactions and cell-cycle behavior in vascular smooth muscle. We examined the relationship between SPARC, senescence-associated VSMC states and vascular remodeling in IA. Methods Public human IA bulk transcriptomic data (44 IA vs 16 control arteries) were analyzed for differential expression and gene set enrichment, with SPARC validated in three independent cohorts. Single-cell RNA sequencing of eight IA and three superficial temporal artery specimens was integrated to define vascular cell states. SenMayo and VSMC contractility scores were combined into a donor-normalized composite score, and the highest decile within each donor was designated senescence-associated. In mice, Sparc deficiency and dasatinib plus quercetin (D + Q) were tested in an elastase-induced IA model (n = 12 per group: sham, IA, Sparc -deficient IA, D + Q-treated IA), with additional analyses in aged mice; outcomes were assessed by blinded observers. Results SPARC was one of 16 genes shared by IA-upregulated genes and FRIDMAN_SENESCENCE_UP (log2FC = + 1.55, FDR = 0.014). Senescence-associated VSMCs were more frequent in IA samples, with inflammatory features and reduced contractile-gene expression; SPARC expression correlated positively with the SenMayo score (r = [X], P = [X]). In mice, aneurysm incidence was 10/12 (83.3%) in untreated mice versus 3/12 (25.0%) with Sparc deficiency (risk ratio [RR] 0.30, 95% CI 0.11–0.83; P = 0.012) and 2/12 (16.7%) with D + Q (RR 0.20, 95% CI 0.06–0.73; P = 0.0033), with reduced senescence staining and preserved contractile markers. In aged mice, Sparc deficiency preserved wall structure better, but the lower incidence was not statistically significant (4/12 vs 8/12; RR 0.50, 95% CI 0.19–1.34; P = 0.22). Conclusions SPARC is associated with senescence-associated VSMC states and arterial wall remodeling in IA, and Sparc deficiency and senolytic treatment were associated with lower aneurysm incidence in mice. Establishing a VSMC-specific mechanism requires further functional validation.