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

Area of Science:

• Vascular Biology
• Developmental Biology
• Genetics

Background:

• Capillary malformations (CM) are congenital vascular lesions linked to somatic mutations in the GNAQ gene.
• Currently, no pharmacotherapy exists for CM, necessitating better disease models.

Purpose of the Study:

• To develop and characterize a conditional mouse model for studying GNAQ-driven capillary malformations.
• To investigate the pathological mechanisms underlying CM using this novel model.

Main Methods:

• Generated a conditional mouse model (R26GT-Gnaq-GFP) for inducible GNAQ p.R183Q expression in endothelial cells (ECs).
• Utilized temporal control (embryonic vs. postnatal induction) to assess GNAQ mutation effects on vascular development.
• Analyzed vascular morphology, EC proliferation, mural cell coverage, extracellular matrix deposition, and gene expression (ESM1, ANGPT2).

Main Results:

• GNAQ p.R183Q expression in ECs induced vascular malformations resembling human CM.
• Embryonic induction led to a lethal vascular phenotype, while postnatal induction caused tortuous, enlarged vessels, particularly in the intestines.
• Mutant ECs showed increased proliferation, abnormal mural cell coverage, altered extracellular matrix, and upregulated ESM1 and ANGPT2 expression, mirroring human CM features.

Conclusions:

• The mouse model validates the causal role of GNAQ p.R183Q in CM pathogenesis.
• The model recapitulates key pathological features of human CM, making it valuable for preclinical drug testing.