在S1PR1-CCN1轴驱动内皮细胞到介质细胞的过渡和血管不稳定性在大脑动脉静脉形形
Ganglei Li1,2,3,4,5, Hongfei Zhang1,2,3,4,5, Mingjian Liu1,2,3,4,5
1Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, No. 12 Wulumuqi Zhong Road, Jing'an District, Shanghai, 200040, China.
European journal of medical research
|November 26, 2025
概括
在S1PR1-CCN1轴调节大脑动脉静脉形 (bAVM) 的进展. S1PR1的丧失促进了内皮细胞到介质酶的过渡 (EndoMT) 和迁移,CCN1调解了这些影响,影响了脑血管的稳定性.
科学领域:
- 血管生物学和病理学
- 细胞可塑性机制 细胞可塑性机制
- 生物分子信号通路是生物分子信号通路.
背景情况:
- 内皮转介质过渡 (EndoMT) 与大脑动脉静脉形形 (bAVMs) 发病和破裂有关.
- 在bAVM中对EndoMT的上游监管机制尚不清楚.
研究的目的:
- 研究S1PR1在调节bAVM中的EndoMT中的作用.
- 为了确定bAVM病原体中S1PR1的下游作用因子.
- 探索S1PR1-CCN1轴作为bAVMs的治疗目标.
主要方法:
- 在公共数据库和人类bAVM组织中分析S1PR1表达.
- 在实验室中使用人类静脉内皮细胞 (HUVECs) 进行S1PR1调制 (敲击/过度表达) 的研究.
- 转录组 (RNA-seq) 和蛋白质组分析,基因本体学 (GO),KEGG和Reactome丰富分析.
- 在斑马鱼模型中进行EndoMT,细胞运动 (迁移,伤口愈合) 和体内验证的测试.
主要成果:
- 在破裂的bAVM组织中减少S1PR1表达.
- 在HUVEC中S1PR1的淘汰诱导了类似EndoMT的表型和增强的迁移;S1PR1过度表达抑制了运动性.
- 鉴定出CCN1 (CYR61) 是S1PR1损失的下游效应因子,介导ECM重塑和细胞骨变化.
- 在体内研究表明,斑马鱼中的s1pr1倒置或ccn1过度表达导致脑血管不稳定 (出血,增生).
- CCN1沉默逆转了S1PR1缺乏细胞中的EndoMT标记物和迁移.
结论:
- S1PR1-CCN1轴是bAVM中内皮质可塑性的关键调节器.
- 失去S1PR1促进了EndoMT和通过CCN1的迁移,导致脑血管不稳定.
- 针对S1PR1-CCN1通路可能为bAVMs提供治疗策略.
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