Endothelial cell expression of mutant Map2k1 causes vascular malformations in mice

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
Patrick J. Smits, Christopher L. Sudduth, Dennis J. Konczyk, Yu Sheng Cheng, Matthew P. Vivero, Harry P. W. Kozakewich, Matthew L. Warman, Arin K. Greene
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引用次数: 6

Abstract

Extracranial arteriovenous malformation (AVM) is a congenital vascular anomaly causing disfigurement, bleeding, ulceration, and pain. Most lesions are associated with somatic MAP2K1 activating mutations in endothelial cells (ECs). The purpose of this study was to determine if EC expression of mutant activated MAP2K1 is sufficient to produce vascular malformations in mice. We generated mice with a ROSA26 allele containing a lox-stop-lox gene trap (GT), Map2k1 cDNA with an activating p.K57N missense mutation, an internal ribosomal entry site, and green fluorescent protein cDNA (R26GT−Map2k1−GFP). We expressed mutant MAP2K1 and GFP in ECs of fetal and newborn mice using Tg-Cdh5Cre or Tg-Cdh5CreER alleles. Tg-Cdh5Cre+/−;R26GT−Map2k1−GFP/+ animals that express mutant MAP2K1 in ECs in utero developed diffuse vascular abnormalities and died by embryonic (E) day 16.5. Tg-Cdh5CreER+/−;R26GT−Map2k1−GFP/+ animals in which mutant MAP2K1 expression was induced in ECs by tamoxifen at postnatal (P) day 1 developed vascular malformations in the brain, ear, and intestines by P23. The lesions consisted of abnormal networks of blood vessels containing recombined and non-recombined ECs. In conclusion, expression of MAP2K1 p.K57N is sufficient to cause vascular malformations in mice. This model can be used to study the malformation process and for pre-clinical pharmacologic studies.

Abstract Image

突变型Map2k1的内皮细胞表达导致小鼠血管畸形
颅外动静脉畸形(AVM)是一种先天性血管畸形,可导致畸形、出血、溃疡和疼痛。大多数病变与内皮细胞(EC)中体细胞MAP2K1激活突变有关。本研究的目的是确定突变激活的MAP2K1的EC表达是否足以在小鼠中产生血管畸形。我们产生了具有ROSA26等位基因的小鼠,该等位基因包含lox-stop lox基因陷阱(GT)、具有激活p.K57N错义突变的Map2k1 cDNA、内部核糖体进入位点和绿色荧光蛋白cDNA(R26GT−Map2k1−GFP)。我们使用Tg-Cdh5Cre或Tg-Cdh5CreER等位基因在胎儿和新生儿小鼠的EC中表达突变的MAP2K1和GFP。Tg-Cdh5Cr+/−;R26GT−Map2k1−GFP/+在子宫内皮细胞中表达突变Map2k1的动物出现弥漫性血管异常,并在胚胎(E)第16.5天死亡。Tg-Cdh5受体+/−;R26GT−Map2k1−GFP/+动物在出生后(P)第1天,三苯氧胺在内皮细胞中诱导突变Map2k1表达,P23导致大脑、耳朵和肠道出现血管畸形。病变由包含重组和非重组内皮细胞的异常血管网络组成。总之,MAP2K1 p.K57N的表达足以引起小鼠的血管畸形。该模型可用于研究畸形过程和临床前药理学研究。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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