DLK1通过内皮前代细胞的Notch1信号传递促进了缺血性血管生成
Ya-Yu You1, Ning Zhang2, Zhuo Wang1,3
1Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Cardiovascular Key Laboratory of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
Acta pharmacologica Sinica
|July 26, 2024
概括
再组合的三角形类似于非正规的诺奇配体1 (DLK1) 通过激活内皮前体细胞中的诺奇1信号,促进血管形成和组织修复. 这项研究澄清了DLK1.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 再生医学是一种再生医学.
背景情况:
- 像德尔塔的非正规的Notch配体1 (DLK1) 参与了生长和发育,但它在血管生成和与Notch信号交互中的作用仍在争论中.
- 在组织缺血的模型中,DLK1的表达被上调,这表明它可能在修复过程中发挥作用.
研究的目的:
- 在后肢缺血症 (HLI) 和心肌梗塞 (MI) 的小鼠模型中研究复合DLK1 (rDLK1) 的亲血管效应.
- 阐明rDLK1-介导血管生成的潜在机制,重点关注其与内皮前代细胞 (EPC) 中的Notch信号通路的相互作用.
主要方法:
- 在接受HLI和MI的C57BL/6小鼠中给予rDLK1或PBS.
- 评估血液输液,肌肉功能和心脏功能.
- 对内皮原生细胞 (EPC) 标记物的分析 (CD34+,KDR+).
- 用rDLK1治疗的EPCs在低毒条件下的ex vivo培养,有或没有Notch抑制剂 (DAPT).
- 评估EPC的扩散,迁移,亡,管形成,活性氧物种水平,ATP含量,线粒体膜潜力和关键线粒体蛋白质 (OPA-1,Mitofusins) 的表达.
主要成果:
- 在HLI小鼠中,rDLK1的使用显著改善了血液 perfusion 和肌肉功能,并在MI小鼠中增强了新血管和心脏功能.
- rDLK1治疗增加了缺血组织中CD34+KDR+EPC的数量,这种效应被DAPT阻止.
- 在体外,rDLK1通过上调Notch1 mRNA和NICD蛋白质来促进EPC增殖,迁移和管形成,同时减少氧化应激并改善线粒体功能.
- 这些由rDLK1介导的亲血管效应依赖于Notch1信号,这是DAPT治疗证实的.
结论:
- 该研究表明,rDLK1具有显著的益血管性质,促进新血管化和缺血性条件下组织修复.
- rDLK1激活了内皮原生细胞中的Notch1信号,增强了它们的功能和生存.
- 这项研究阐明了DLK1促进血管生成的机制,突出了其在治疗缺血性疾病中的潜在治疗价值.
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