A single-cell atlas of intracranial aneurysm progression identifies a dysfunctional VSMC subpopulation associated with rupture risk.

BACKGROUND

Intracranial aneurysm (IA) rupture is a life-threatening event. While inflammation is implicated, the cellular mechanisms associated with progression from stable lesion to rupture remain poorly defined at single-cell resolution.

METHODS

We performed single-cell RNA sequencing (scRNA-seq) on a mouse model spanning sham, formed, and ruptured IA stages. Computational analyses included trajectory inference, cell-cell communication analysis, and metabolic scoring. Key findings were validated using human IA bulk RNA-seq data and protein-level assays on matched clinical tissues.

RESULTS

Our single-cell atlas revealed a progressive "inflammatory-lytic" microenvironment marked by immune cell infiltration and vascular smooth muscle cell (VSMC) depletion. We identified a metabolically specialized VSMC subpopulation (VSMC_0) that was selectively lost in formed and ruptured aneurysms. Pseudotime analysis indicated VSMC differentiation blockade, associated with downregulation of the structural genes actin alpha2, smooth muscle (ACTA2) and prolyl 4-hydroxylase subunit alpha2 (P4HA2), which correlated with irregular aneurysm shape a strong clinical predictor of rupture risk. Cell communication analysis positioned VSMC_0 as a signaling hub to macrophages, suggesting a feed-forward inflammatory loop. These findings were validated in human IAs tissues.

CONCLUSION

Our study identifies VSMC phenotypic dysregulation as a key correlate of IA instability, linking molecular deficits to clinical rupture predictors. This reframes IA as a disorder of vascular cellular identity and communication, revealing potential therapeutic targets for aneurysm stabilization.