Endothelial cell expression of mutant Map2k1 causes vascular malformations in mice

Area of Science:

• Vascular Biology
• Genetics
• Developmental Biology

Background:

• Extracranial arteriovenous malformations (AVMs) are congenital vascular anomalies.
• These AVMs often present with disfigurement, bleeding, ulceration, and pain.
• Somatic MAP2K1 activating mutations in endothelial cells (ECs) are frequently associated with AVMs.

Purpose of the Study:

• To determine if endothelial cell expression of mutant activated MAP2K1 is sufficient to cause vascular malformations in a mouse model.
• To establish a preclinical model for studying AVM pathogenesis and evaluating potential therapies.

Main Methods:

• Generated a novel mouse model (R26^{GT-Map2k1-GFP}) expressing a constitutively active MAP2K1 (p.K57N) mutation and GFP in ECs.
• Utilized Cre-lox recombination systems (Tg-Cdh5Cre and Tg-Cdh5CreER) to control the timing and location of mutant MAP2K1 expression in ECs.
• Analyzed vascular abnormalities in fetal and postnatal mice following in utero or tamoxifen-induced expression of mutant MAP2K1.

Main Results:

• In utero expression of mutant MAP2K1 in ECs led to diffuse vascular abnormalities and embryonic lethality by E16.5.
• Postnatal induction of mutant MAP2K1 in ECs resulted in the development of brain, ear, and intestinal vascular malformations by P23.
• Histological analysis revealed abnormal blood vessel networks composed of both recombined and non-recombined ECs.

Conclusions:

• Endothelial cell expression of the MAP2K1 p.K57N mutation is sufficient to induce vascular malformations in mice.
• This mouse model accurately recapitulates key features of AVMs.
• The developed model serves as a valuable tool for investigating AVM development and for preclinical drug testing.