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脑洞形是由MEKK3-KLF2/4信号的内皮增长引起的

Zinan Zhou¹, Alan T Tang¹, Weng-Yew Wong²

¹Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA.

|March 31, 2016

概括

在内皮细胞中MEKK3信号和KLF2/4功能的增加导致脑洞形 (CCM). 针对这种途径可能为中风和患者提供新的CCM治疗方法.

科学领域:

血管生物学
遗传学
疾病的分子机制

背景情况:

脑洞形 (CCM) 是导致中风和的血管缺陷.
CCM是由KRIT1,CCM2或PDCD10的损失造成的,形成了一个适应器复合体.
正确的驱动CCM病变的分子机制被争论,并提出了Rho,SMAD,Wnt/β-catenin信号传递和内皮介质转换 (EndMT) 的作用.

研究的目的:

调查MEKK3信号在CCM病变中的作用.
确定MEKK3目标Klf2和Klf4在CCM形成中的参与.
探索CCM疾病的潜在治疗点.

主要方法:

使用新生儿小鼠模型的CCM疾病.
在CCM病变的内皮细胞中分析了基因表达 (Klf2,Klf4) 和信号通路活性 (Rho,SMAD,Wnt).
在小鼠中执行内皮特异性基因淘汰Map3k3 (Mekk3),Klf2和Klf4.
检查了人类CCM病变的KLF2/4表达,并分析了导致疾病的CCM2突变对MEKK3相互作用的影响.

主要成果:

在小鼠早期的CCM病变中,MEKK3基因Klf2和Klf4的表达增加,Rho活性升高,ADAMTS蛋白酶活性升高.
在早期CCM形成中没有发现EndMT或增加SMAD/ Wnt信号的证据.
内皮特异性删除Map3k3,Klf2或Klf4显著降低了CCM病变的形成,使Rho活性正常化,并预防了致死性.
人类CCM病变显示内皮KLF2和KLF4的表达增加.
一个致病性CCM2突变破坏了MEKK3的相互作用,但没有破坏CCM复合体的稳定.

结论:

在内皮细胞中获得MEKK3信号和随后的KLF2/4激活是CCM病变的关键驱动因素.
在早期CCM形成中,EndMT,SMAD和Wnt信号不是主要的机制.
MEKK3-KLF2/4通路代表了大脑洞腔形的一个有前途的治疗标.

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