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动脉静脉形形Map2k1突变影响血管生成

Christopher L Sudduth¹, Patrick J Smits¹, Matthew P Vivero¹

¹Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA, 02115, USA.

Scientific reports

|July 8, 2023

概括

在MAP2K1体质突变导致动脉静脉形 (AVMs). 这项研究揭示了内皮细胞中的突变MAP2K1如何改变基因表达,影响血管发育和AVM形成至关重要的途径.

科学领域:

血管生物学血管生物学
遗传学是一个遗传学.
发育生物学发展生物学

背景情况:

在MAP2K1的体活性突变与内皮细胞 (EC) 功能障碍有关,导致额外动脉静脉形 (AVM).
之前的工作建立了一个小鼠模型 (R26^{GT-Map2k1-GFP/+}) 具有可诱导的表达构成性活跃的MAP2K1 (p.K57N) 在EC,证明其足以引起血管形.

研究的目的:

阐明突变MAP2K1驱动AVM发展的分子机制.
为了确定关键的基因和受MAP2K1过度表达影响的途径在早期产后发育期间ECs.

主要方法:

在出生后第一天的小鼠小鼠的EC中,突变MAP2K1 (p.K57N) 的诱导表达.
在出生后的第九天对突变型和野生型 littermates 的脑EC进行RNA测序 (RNA-seq) 分析.
免疫染用于验证差异性基因表达,特别是对于COL15A1.1.

主要成果:

在EC中突变MAP2K1的过度表达改变了超过1600个基因的转录丰度.
在诸如Col15a1 (39倍) 和Itgb3 (24倍) 等基因中观察到显著的折叠变化.
基因本体学分析揭示了血管生成关键途径的丰富,包括细胞迁移,粘附,细胞外矩阵组织,管形成和血管生成.

结论:

突变MAP2K1表达对EC转录组产生深远影响,导致血管发育必不可少的基因发生变化.
鉴定出差异表达的基因和途径为AVM提供了潜在的治疗点.
对这些特定基因和途径的进一步调查将有助于更好地了解AVM的发病过程.

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