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

Capillary malformation (CM) is a congenital, non-hereditary lesion composed of enlarged and tortuous blood vessels. CM is associated with a somatic GNAQ p.R183Q activating mutation in endothelial cells (EC). Cutaneous CMs are present in 1/300 infants and in 55-70% of CM cases soft tissue overgrowth is observed. Pharmacotherapy for CM does not exist. Here we report a conditional mouse model allowing the simultaneous tissue specific expression of GNAQ p.R183Q and GFP from the R26 locus ( R26 GT-Gnaq-GFP ). We show that expression of GNAQ p.R183Q in ECs results in vascular malformations with features similar to human CM lesions. GNAQ p.R183Q expression during embryonic development ( Tg-Cdh5Cre) resulted in a severe vascular phenotype, lethal by embryonic (E) 16.5. Induction of mutant GNAQ expression in ECs at postnatal (P) day 1 ( Tg-Cdh5CreER) led to tortuous and enlarged blood vessels, most noticeable in the intestines. GNAQ p.R183Q/GFP expressing ECs co-localized with lesions and displayed increased proliferation. Mutant ECs had abnormal mural cell coverage and abnormal pericellular extracellular matrix deposition, which was confirmed in human CM samples. Similar to human CM they displayed strong expression of the tip cell marker ESM1 and increased ANGPT2 expression. In conclusion, GNAQ p.R183Q expression in murine ECs causes vascular malformations supporting the causality of the mutation for CM. The lesions recapitulate multiple features of human CM, making the mouse model suitable for the preclinical testing of future CM pharmacotherapy.