Abstract
Nonsyndromic capillary malformations (CM) are seen predominantly in skin. In Sturge-Weber Syndrome (SWS), CMs occur in the skin, leptomeninges of the brain, and choroid of the eye. >90% of CM are caused by a somatic mutation-GNAQ p.R183Q, the gene encoding the G-protein subunit Gα(q). Longitudinal MRI of the brain in one SWS patient suggests developing vascular permeability. We modeled this in a transendothelial electrical resistance assay and found endothelial cells with GNAQ p.R183Q (EC-R183Q) exhibited increased permeability compared to EC wild-type. Increased vascular permeability was confirmed in a Gnaq p.R183Q mouse model. Knockdown of elevated angiopoietin-2 (ANGPT2) in EC-R183Q partially restored the EC barrier, as did a MEK1,2 inhibitor, implicating MAPK/ERK signaling. The combination of ANGPT2 knockdown and trametinib further restored the EC barrier in an additive manner. indicating the two operate in separate pathways. In summary, we found that EC-R183Q exhibits increased permeability, reflecting the compromised endothelial barrier in CMs.