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<p>Capillary malformations (CMs) are congenital vascular lesions caused by somatic mutations in the <i>GNAQ</i> 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 <i>GNAQ</i>-driven vascular malformations, including Sturge-Weber syndrome.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月4日

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  • Tong Xu,
  • Vera Janssen,
  • Nathalie R. Reinhard,
  • Paula Sobrevals-Alcaraz,
  • Robert M. van Es,
  • Annett de Haan,
  • Julian de Swart,
  • Martijn Wehrens,
  • Hannah de Kraker,
  • Albert Wolkerstorfer,
  • Chantal M. A. M. van der Horst,
  • Harmjan R. Vos,
  • Stephan Huveneers

摘要

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.