在肺内皮细胞中,HDAC6和ERK/ADAM17调节了VEGF诱导的NOTCH信号
Sheng Xia1, Heather L Menden1, Sherry M Mabry1
1Division of Neonatology, Department of Pediatrics, Children's Mercy, Kansas City, MO 64108, USA.
Cells
|September 28, 2023
概括
基斯脱乙酶6 (HDAC6) 通过控制内皮细胞中NOTCH信号传递来调节血管生成. 抑制HDAC6会改变NICD乙化和SNW1结合,影响肺血管生成和肺膜化.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 生理学 生理学 生理学
背景情况:
- 血管新生对于生理和病理过程至关重要,由血管内皮生长因子 (VEGF) 调节.
- 基因组脱乙酶6 (HDAC6),一种脱乙酶,影响细胞质信号传递,是调节血管生成的潜在目标.
- 需要进一步阐明HDAC6在VEGF诱导的内皮细胞 (EC) NOTCH信号中的作用.
研究的目的:
- 调查HDAC6是否通过NOTCH细胞内细胞内细胞质域 (NICD) 的乙化调节VEGF诱导的NOTCH信号.
- 确定HDAC6抑制对NICD稳定性,NICD-SNW1结合以及随后的NOTCH转录反应的影响.
主要方法:
- 利用肺内皮细胞 (EC) 研究VEGF诱导的NOTCH信号.
- 采用HDAC6抑制并评估NICD乙化和稳定性.
- 研究了NICD和SNW1.1之间的相互作用.
- 进行了体外血管生成测定和体内研究,使用新生小鼠接受全身HDAC6抑制剂治疗.
主要成果:
- 在EC中VEGF诱导的NICD转录反应涉及ERK1/2,ADAM17和DLL4.
- 抑制HDAC6导致NICD乙化和稳定.
- 抑制HDAC6抑制了NICD-SNW1结合,这对于NOTCH转录反应至关重要.
- 在体外,HDAC6抑制抑制了肺部EC血管生成.
- 在新生小鼠中,系统性HDAC6抑制显著改变了血管新生和膜化.
结论:
- HDAC6通过调节NICD乙化和稳定性来调节VEGF诱导的血管生成.
- HDAC6抑制通过影响NICD-SNW1结合影响NOTCH信号传递,从而抑制转录反应.
- 这些发现强调了HDAC6作为血管生成和肺部发育的关键调节剂,具有治疗潜力.
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