An endothelial specific mouse model for the capillary malformation mutation Gnaq p.R183Q

Area of Science:

• Vascular Biology
• Developmental Biology
• Genetics

Background:

• Capillary malformation (CM) is a congenital vascular anomaly linked to somatic GNAQ p.R183Q mutations in endothelial cells (ECs).
• Existing treatments for CM are limited, highlighting the need for new therapeutic strategies.
• Soft tissue overgrowth frequently accompanies CM, affecting 55-70% of cases.

Purpose of the Study:

• To develop and characterize a conditional mouse model for studying capillary malformations.
• To investigate the role of GNAQ p.R183Q mutations in endothelial cells in causing vascular malformations.
• To establish a preclinical platform for testing potential CM therapies.

Main Methods:

• Generated a conditional mouse model enabling tissue-specific expression of GNAQ p.R183Q and GFP.
• Utilized Cre-lox recombination systems (Tg-Cdh5Cre and Tg-Cdh5CreER) for temporal control of gene expression in ECs.
• Analyzed vascular phenotypes, EC proliferation, mural cell coverage, extracellular matrix deposition, and gene expression in mutant mice and human CM samples.

Main Results:

• Expression of GNAQ p.R183Q in ECs induced vascular malformations mimicking human CM.
• Embryonic GNAQ expression led to lethal vascular defects, while postnatal induction caused significant intestinal vascular abnormalities.
• Mutant ECs exhibited increased proliferation, abnormal mural cell support, altered extracellular matrix, and upregulated tip cell markers (ESM1, ANGPT2), consistent with human CM.

Conclusions:

• Somatic GNAQ p.R183Q mutations in ECs are causative of vascular malformations resembling human CM.
• The developed mouse model accurately recapitulates key pathological features of human CM.
• This model serves as a valuable tool for preclinical evaluation of novel pharmacotherapies for CM.