Endothelial cell expression of mutant Map2k1 causes vascular malformations in mice

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..

Medienart:

E-Artikel

Erscheinungsjahr:

2022

Erschienen:

2022

Enthalten in:

Zur Gesamtaufnahme - volume:26

Enthalten in:

Angiogenesis - 26(2022), 1 vom: 16. Aug., Seite 97-105

Sprache:

Englisch

Beteiligte Personen:

Smits, Patrick J. [VerfasserIn]
Sudduth, Christopher L. [VerfasserIn]
Konczyk, Dennis J. [VerfasserIn]
Cheng, Yu Sheng [VerfasserIn]
Vivero, Matthew P. [VerfasserIn]
Kozakewich, Harry P. W. [VerfasserIn]
Warman, Matthew L. [VerfasserIn]
Greene, Arin K. [VerfasserIn]

Links:

Volltext [lizenzpflichtig]

BKL:

44.85$jKardiologie$jAngiologie

Themen:

Arteriovenous malformation
Cdh5Cre
Cdh5CreER
Conditional ROSA allele
Endothelial
Map2k1
Murine
Vascular

Anmerkungen:

© The Author(s), under exclusive licence to Springer Nature B.V. 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

doi:

10.1007/s10456-022-09853-6

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

OLC2133829970

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