Introduction of Mutant GNAQ into Endothelial Cells Induces a Vascular Malformation Phenotype with Therapeutic Response to Imatinib

SIMPLE SUMMARY: Mutations in GNAQ underlie vascular malformations, including Sturge-Weber disease. In order to develop novel therapies for lesions with mutant GNAQ, we introduced mutant GNAQ into MS1 endothelial cells. Mutant GNAQ conferred a novel phenotype of progressive vascular malformations in mice. Chromatin analysis revealed upregulation of C-Kit in the vascular endothelial cells, and we found C-Kit to be highly expressed in Sturge-Weber disease. Given that imatinib is an FDA approved multikinase inhibitor that blocks C-Kit, we evaluated it in our mouse model, and showed that imatinib had activity against these vascular malformations. Repurposing imatinib should be evaluated in clinical trials, including Sturge-Weber disease. ABSTRACT: GNAQ is mutated in vascular and melanocytic lesions, including vascular malformations and nevi. No in vivo model of GNAQ activation in endothelial cells has previously been described. We introduce mutant GNAQ into a murine endothelial cell line, MS1. The resultant transduced cells exhibit a novel phenotype in vivo, with extensive vasoformative endothelial cells forming aberrant lumens similar to those seen in vascular malformations. ATAC-seq analysis reveals activation of c-Kit in the novel vascular malformations. We demonstrate that c-Kit is expressed in authentic human Sturge–Weber vascular malformations, indicating a novel druggable target for Sturge–Weber syndrome. Since c-Kit is targeted by the FDA-approved drug imatinib, we tested the ability of imatinib on the phenotype of the vascular malformations in vivo. Imatinib treated vascular malformations are significantly smaller and have decreased supporting stromal cells surrounding the lumen. Imatinib may be useful in the treatment of human vascular malformations that express c-Kit, including Sturge–Weber syndrome.