拉特罗菲林-2在内皮结处调解液体剪切应力机制传导
Keiichiro Tanaka1, Minghao Chen2, Andrew Prendergast2
1Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, 06511, USA. keiichiro.tanaka@yale.edu.
The EMBO journal
|June 17, 2024
概括
内皮细胞通过拉托菲林-2 (Lphn2) 感知血液流动,激活G蛋白和下游信号,对血管发育和心血管健康至关重要.
科学领域:
- 心血管生物学 心血管生物学
- 细胞机械传导 细胞机械传导
- 分子信号传输的方法
背景情况:
- 内皮细胞对血流剪切压力做出反应,对血管健康和疾病至关重要.
- 一个已知的细胞结点复合体 (PECAM-1,VE-cadherin,VEGFRs,Plexin D1) 调解了反应,但一个上游机械传感器是未知的.
研究的目的:
- 为了识别上游机械传感器,以响应流体剪切应力,启动内皮细胞信号.
- 阐明连接机械感知与下游结合复合体激活和血管生理学的途径.
主要方法:
- siRNA对Gα子单元的选,以识别关键信号蛋白.
- 开发一种新型激活试验,以测量G蛋白通过流动的激活.
- 使用映射的Gα残留物用于识别上游G蛋白结合受体 (GPCR) 的亲和性净化.
- 在小鼠和斑马鱼体内研究,包括内皮特异性淘汰模型.
- 分析人类遗传数据与心血管疾病的相关性.
主要成果:
- Gαi2和Gαq/11对于在流动下激活内皮结合综合体至关重要.
- 流动直接激活这些G蛋白,特定的残留物被绘制为激活.
- 拉特罗菲林-2 (Lphn2 / ADGRL2) 被确定为上游GPCR,用于PECAM-1下游信号.
- 拉特罗菲林-2对于流量依赖的血管生成和动脉重塑在体内至关重要.
- 人类遗传数据将Adgrl2与心血管疾病联系起来.
结论:
- 拉特罗菲林-2 作为主要的机械传感器,以响应血液流动启动G蛋白信号传递.
- 这条通路对内皮功能,血管发育和动脉重塑至关重要.
- 这种途径的失调与心血管疾病有关.
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