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
{"title":"Endothelial cell expression of mutant Map2k1 causes vascular malformations in mice","authors":"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","doi":"10.1007/s10456-022-09853-6","DOIUrl":null,"url":null,"abstract":"<div><p>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 <i>ROSA26</i> allele containing a lox-stop-lox gene trap (GT), <i>Map2k1</i> cDNA with an activating p.K57N missense mutation, an internal ribosomal entry site, and green fluorescent protein cDNA (<i>R26</i><sup><i>GT−Map2k1−GFP</i></sup>). We expressed mutant MAP2K1 and GFP in ECs of fetal and newborn mice using <i>Tg-Cdh5Cre</i> or <i>Tg-Cdh5CreER</i> alleles. <i>Tg-Cdh5Cre</i><sup>+/−</sup><i>;R26</i><sup><i>GT−Map2k1−GFP/</i>+</sup> animals that express mutant MAP2K1 in ECs in utero developed diffuse vascular abnormalities and died by embryonic (E) day 16.5. <i>Tg-Cdh5CreER</i><sup>+/−</sup><i>;R26</i><sup><i>GT−Map2k1−GFP/</i>+</sup> 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.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":null,"pages":null},"PeriodicalIF":9.2000,"publicationDate":"2022-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-022-09853-6.pdf","citationCount":"6","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Angiogenesis","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s10456-022-09853-6","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PERIPHERAL VASCULAR DISEASE","Score":null,"Total":0}
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.
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.