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Background <p>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.</p> Methods <p>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.</p> Results <p>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 (<i>ACTA2</i>) and prolyl 4-hydroxylase subunit alpha2 (<i>P4HA2</i>), 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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月23日

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  • Xiangrong Chen,
  • Bikun Liu,
  • Xiaofeng Zhou,
  • Zongtao Wu,
  • Dongze Xu,
  • Jingcheng Zhan,
  • Jinliang Liu,
  • Mao Ling,
  • Fan Liu

摘要

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.