Calcineurin-NFAT-DSCR1.4 signaling as druggable axis in Gαq-R183Q-driven capillary malformations

Abstract

Capillary malformations (CMs) are congenital vascular lesions caused by somatic mutations in the GNAQ gene, most frequently resulting in a p.R183Q substitution in the Gαq protein in endothelial cells. However, the downstream signaling pathways by which Gαq-R183Q impairs vascular function remain poorly defined. To address this, we generated human dermal endothelial cells lacking endogenous Gαq and expressing the Gαq-R183Q mutant. Next, using SILAC-based quantitative proteomics, we mapped the Gαq-R183Q-induced endothelial phosphoproteome. These analyses identified aberrant activation of the Calcineurin-NFAT-DSCR1.4 signaling cascade as a key pathogenic feature. NFAT dysregulation and DSCR1 expression in endothelial cells were confirmed in patient-derived biopsies. Pharmacological inhibition of Calcineurin with tacrolimus partially normalized NFAT signaling in Gαq-R183Q endothelial cells. Strikingly, genetic depletion of DSCR1 in Gαq-R183Q cells fully restored Calcineurin/NFAT signaling and enabled proper endothelial migration and angiogenic sprouting, highlighting DSCR1 as a critical effector of Gαq-R183Q signaling in CMs. These findings reveal a druggable signaling circuit downstream of Gαq-R183Q that may serve as a foundation for future therapies targeting GNAQ-driven vascular malformations, including Sturge-Weber syndrome.