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Flk1 缺乏和缺氧协同促进内皮功能障碍,血管重塑和肺高血压
Tatsuya Akiyama1,2, Taketaro Sadahiro1, Yu Yamada1
1Department of Cardiology (T.A., T.S., Y.Y., R.F., Y.A., K.N., S.H., S.S., M.I.), Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
Arteriosclerosis, thrombosis, and vascular biology
|August 3, 2023
概括
血管内皮生长因子受体1 (Flk1) 缺乏通过促进动脉重塑,使肺高血压恶化. 在内皮细胞 (ECs) 中Flk1的损失加剧了EC功能障碍和在缺氧诱导的肺高血压中血管重塑.
科学领域:
- 心血管研究研究心血管研究
- 肺部医学 肺部医学
- 细胞生物学 细胞生物学
背景情况:
- 肺高血压 (PH) 和动脉动脉重塑的机制尚不清楚.
- 血管内皮生长因子 (VEGF) 通过内皮细胞 (ECs) 上的 Flk1 (胎儿肝激酶 1) 和 Flt1 (fms-like tyrosine kinase 1) 传递信号,与PH的发病有关.
- 在PH期间,Flk1和Flt1在肺血管中的时空表达和功能作用尚不清楚.
研究的目的:
- 在低氧诱导的PH期间,研究在肺血管中Flk1和Flt1的时空表达.
- 阐明内皮Flk1在肺血管改造和PH的发展中的作用.
主要方法:
- 使用多个记者小鼠 (Flk1-GFP,Flt1-DsRed,双Tg) 来追踪低氧诱导PH中的Flk1和Flt1表达.
- 使用Cdh5CreERT2/Flk1f/f/番茄系统进行功能研究,生成了EC特定的Flk1淘汰赛 (Flk1-KO) 鼠标.
- 在慢性缺氧下从Flk1-KO小鼠的肺EC上进行了血统追踪和RNA测序.
主要成果:
- Flk1在小肺血管 (动脉) 的EC中特别表达,而Flt1表达范围更广.
- 缺氧增加了Flk1+ ECs的增殖;在ECs中Flk1的删除加剧了缺氧诱导的EC功能障碍,亡,并减少了EC数量.
- flk1缺乏促进了动脉中枢的加厚,新极端的形成,并恶化了PH,新极端细胞源自flk1-KO ECs.
- RNA测序揭示了细胞周期,衰老/亡和细胞因子通路的协同激活,抑制了粘附/血管生成,促进了血管重塑.
结论:
- Flk1和Flt1在肺EC中表现出不同的表达模式.
- 结合的Flk1缺乏和缺氧失调动脉动 ECs,驱动血管重塑.
- 内皮Flk1功能障碍对肺动脉小动脉中先进的血管重塑有显著的贡献,这表明了治疗点.
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