147. MAP2K1 Mutant Murine Model Recapitulates Human Cutaneous Arteriovenous Malformation

Abstract

PURPOSE: Arteriovenous malformation (AVM) is a congenital vascular anomaly caused by somatic activating mutations in MAP2K1 in endothelial cells (ECs). AVMs cause deformity, bleeding, ulceration, pain, and death. We recently generated a conditional Map2k1-K57N mouse model by inserting a Map2k1-K57N cDNA-IRES (independent ribosomal entry side)-GFP cassette in the mouse ROSA locus under control of the CAG promoter. Mice develop vascular malformations in the brain, ear, and intestines. However, brain lesions cause lethality between 23-71 days after birth and the animals do not develop large AVM lesions in the skin. The purpose of this study was to extend the lifespan of mutant animals and study whether they developed significant cutaneous AVMs over time. METHODS: We inserted a LoxP flanked gene trap (GT) downstream of the promotor to prevent expression of the mutant allele (R26GT-Map2k1-GFP). Using the tamoxifen inducible EC specific Tg-Cdh5CreER transgene, we activated Map2k1-K57N expression in ECs at P1. In an effort to increase the lifespan of the mice, we reduced the amount of tamoxifen to 1/10th of our previous dose (5 ul of 1 ug/ul 4-OH-tamoxifen in acetone) applied topically to the left ear. RESULTS: We obtained 1 Tg-Cdh5Cre+/-;R26GT-Map2k1-GFP/+ mouse that survived 4 months after birth. The mouse exhibited 2 large cutaneous AVMs; 1 involved the orbital area and 1 affected the neck. The mouse also exhibited intestinal lesions but not brain malformations. The integument lesions shared a similar phenotype to human AVM. CONCLUSION: Decreasing the tamoxifen dose of Tg-Cdh5Cre+/-;R26GT-Map2k1-GFP/+ mice extends their lifespan. These mice develop large AVMs of the integument suggesting the lesions behave similarly to human lesions, progressing from Stage 1 to Stage 2 as mice age. This successful murine model can be used to study the pathophysiology of AVM as well as to test novel pharmacotherapy against the lesion.