内皮KLF15/VASN轴通过激活Notch1信号来抑制血管生成
Jia Zhang1,2, Jia-Jia Zhao1, Han-Dan Zhou1
1Department of Cardiovascular Medicine, Department of Hypertension, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China (J.Z., J.-J.Z., H.-D.Z., J.C., M.-N.H., J.-G.W., P.-J.G., X.-D.L.).
Circulation research
|April 29, 2025
概括
克鲁佩尔样因子15 (KLF15) 通过激活通过素 (VASN) 的Notch1信号来负面调节血管生成. 这个KLF15/VASN通路为血管生成相关疾病和瘤提供了潜在的治疗点.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 心血管研究研究心血管研究
背景情况:
- 血管生成,即新血管的形成,是一个复杂的过程,由内皮细胞中的转录因子调节.
- 克鲁佩尔样因子15 (KLF15) 在心血管疾病中起着关键作用,但其在血管生成中的特定功能以前是未知的.
研究的目的:
- 研究KLF15在调节血管生成中的作用.
- 为了确定下游效应因子和KLF15控制内皮细胞功能的分子机制.
主要方法:
- 产生内皮细胞特异性KLF15淘汰 (EC-KLF15 KO) 和素 (VASN) 淘汰 (EC-VASN KO) 鼠标.
- 视网膜血管生成和瘤移植模型被用于评估血管生成潜力.
- 用RNA测序,ATAC-seq和ChIP-seq来阐明KLF15的调节网络,并将VASN确定为目标.
- 为了评估内皮细胞功能,进行了体外测试 (增殖,伤口愈合,管道形成,发芽).
主要成果:
- 发现KLF15在体内和体外负面调节视网膜血管生成.
- KLF15通过在富含GC的促进体上打开染色质来直接激活VASN表达.
- VASN抑制了内皮细胞的血管功能,对Dll4诱导的Notch1信号传递至关重要.
- VASN的EGF类域与Notch1相互作用,激活Notch1信号,并抑制血管生成.
结论:
- KLF15/VASN信号轴通过Notch1激活来负面调节血管生成.
- KLF15和VASN代表了异常血管生成的疾病的潜在治疗点,包括瘤.
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