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NCoR1通过改变Notch信号来限制血管生成能力
Tom Teichmann1, Pedro Malacarne1, Simonida Zehr1
1Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main 60590, Germany; German Center for Cardiovascular Research (DZHK), Partner site Rhein Main, Frankfurt am Main, Germany.
Journal of molecular and cellular cardiology
|February 15, 2024
概括
向核受体核心压缩剂1 (NCoR1) 增强内皮细胞血管功能,独立于VEGF信号传递. 减少NCoR1促进尖端细胞基因表达,改善血管形成.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 血管新生研究研究
背景情况:
- 核心压缩器通过染色质紧缩来调节基因表达.
- 向内皮细胞表型对于控制血管功能至关重要.
- 核核抑制剂是内皮细胞中基因表达的关键调节剂.
研究的目的:
- 研究核核心压缩剂在人类静脉内皮细胞 (HUVECs) 中的作用.
- 为了确定是否准核心压缩蛋白可以改善内皮血管功能.
- 阐明NCoR1对血管生成的影响背后的分子机制.
主要方法:
- RNA测序 (RNA-seq) 用于在HUVECs中识别高度表达的核心压缩体.
- 基因淘汰和淘汰策略来评估核心压缩机功能.
- RNA-seq和ATAC-seq用于基因表达和染色体可访问性分析.
- 球形发芽试验和对抗试验.
- 近距离结合试验和光酶试验用于研究蛋白质相互作用和转录活性.
主要成果:
- 核受体核心压缩剂1 (NCoR1),SMRT和REST在HUVEC中表达很高.
- 与SMRT或REST枯竭不同,NCoR1枯竭显著增加了内皮血管生成能力.
- 抑制NCoR1对血管新生相关基因进行上调,特别是尖端细胞基因 (例如ESM1,DLL4,NOTCH4),独立于VEGF信号传递.
- 丢失NCoR1促进了球形发芽的尖端细胞定位.
- NCoR1直接与RBPJk结合,其耗尽可以增强RBPJk活动和Notch信号传输.
- NOTCH4下调取消了NCoR1敲击的亲血管效应.
结论:
- 降低NCoR1表达是一种有前途的策略,可以增强内皮血管功能.
- NCoR1通过独立于VEGF的Notch信号通路调节血管生成.
- 准NCoR1为促进血管形成提供了一种新的治疗方法.
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