Characterization of patient-derived GNAQ mutated endothelial cells from capillary malformations.

Capillary malformations (port-wine stains) are congenital skin lesions that are characterized by dilated capillaries and post-capillary venules. Capillary malformations are caused by altered functioning of the vascular endothelium. Somatic genetic mutations have predominantly been identified in the endothelial cells of capillary malformations, providing an opportunity for the development of targeted therapies. However, there is currently limited in-depth mechanistic insight in the pathophysiology and a lack of pre-clinical research approaches. In a mono-centre exploratory study of 17 adult patients with capillary malformations, we found somatic mutations in the GNAQ [p.R183Q, p.R183G or p.Q209R] or GNA11 [p.R183C] genes. We applied an endothelial-selective cell isolation protocol to culture primary endothelial cells from skin biopsies from these patients. In 3 out of the 17 cases we succesfully expanded patient-derived cells in culture, while maintaining endothelial specificity as demonstrated by Vascular Endothelial (VE)-cadherin immunostainings. In addition, we tested the angiogenic capacity of endothelial cells from a patient with a GNAQ [p.R183G]. These proof-of-principle results reveal that primary cells isolated from capillary malformations may represent a functional research model to investigate the role of endothelial somatic mutations in the aetiology of capillary malformations, but improved isolation and culture methodologies are urgently needed to advance the field.