Aims While previous single-cell RNA sequencing (scRNA-seq) studies have attempted to dissect intracranial aneurysm (IA), the primary molecular mechanism for IA pathogenesis remains unknown. Here, we uncovered the alterations of cellular compositions, especially the transcriptome changes of vascular endothelial cells (ECs), in human IA. Methods and results We performed scRNA-seq to compare the cell atlas of sporadic IA and the control artery. The transcriptomes of 43 462 cells were profiled for further analysis. In general, IA had increased immune cells (T/NK cells, B cells, myeloid cells, mast cells, neutrophils) and fewer vascular cells (ECs, vascular smooth muscle cells, and fibroblasts). Based on the obtained high-quantity and high-quality EC data, we found genes associated with angiogenesis in ECs from IA patients. By EC-specific expression of candidate genes in vivo, we observed the involvement of angpt2a in causing cerebral vascular abnormality. Furthermore, an IA zebrafish model mimicking the main features of human IA was generated through targeting pdgfrb gene, and knockdown of angpt2a alleviated the vascular dilation in the IA zebrafish model. Conclusion By performing a landscape view of the single-cell transcriptomes of IA and the control artery, we contribute to a deeper understanding of the cellular composition and the molecular changes of ECs in IA. The implication of angiogenic regulator ANGPT2 in IA formation and progression, provides a novel potential therapeutical target for IA interventions.

中文翻译：

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单细胞分析揭示了血管内皮细胞-内源性 ANGPT2 在人颅内动脉瘤中的影响


目的 虽然以前的单细胞 RNA 测序 （scRNA-seq） 研究试图解剖颅内动脉瘤 （IA），但 IA 发病机制的主要分子机制仍然未知。在这里，我们发现了人类 IA 中细胞组成的改变，尤其是血管内皮细胞 （EC） 的转录组变化。方法和结果 我们进行了 scRNA-seq 比较散发性 IA 和对照动脉的细胞图谱。对 43 462 个细胞的转录组进行分析以供进一步分析。一般来说，IA 的免疫细胞 （T/NK 细胞、B 细胞、髓样细胞、肥大细胞、中性粒细胞） 增加，血管细胞 （ECs、血管平滑肌细胞和成纤维细胞） 减少。基于获得的大量和高质量的 EC 数据，我们发现了 IA 患者 ECs 中与血管生成相关的基因。通过候选基因在体内的 EC 特异性表达，我们观察到 angpt2a 参与引起脑血管异常。此外，通过靶向 pdgfrb 基因生成模拟人类 IA 主要特征的 IA 斑马鱼模型，敲除 angpt2a 减轻了 IA 斑马鱼模型中的血管扩张。结论 通过对 IA 和对照动脉的单细胞转录组进行横向视图，我们有助于更深入地了解 IA 中 ECs 的细胞组成和分子变化。血管生成调节因子 ANGPT2 在 IA 形成和进展中的作用，为 IA 干预提供了新的潜在治疗靶点。