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

Angiogenesis. 2026 Feb 4;29(2):16. doi: 10.1007/s10456-026-10029-9.

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.

Keywords: Angiogenesis; Endothelial cell; FK506; GNAQ p.R183Q; Migration; Sturge-Weber syndrome; Tacrolimus; Vascular malformation.

MeSH terms

  • Calcineurin* / metabolism
  • Capillaries* / abnormalities
  • Capillaries* / metabolism
  • Capillaries* / pathology
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • GTP-Binding Protein alpha Subunits, Gq-G11* / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11* / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins* / metabolism
  • Muscle Proteins* / genetics
  • Muscle Proteins* / metabolism
  • NFATC Transcription Factors* / genetics
  • NFATC Transcription Factors* / metabolism
  • Signal Transduction* / drug effects
  • Vascular Malformations* / drug therapy
  • Vascular Malformations* / genetics
  • Vascular Malformations* / metabolism
  • Vascular Malformations* / pathology

Substances

  • NFATC Transcription Factors
  • Calcineurin
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • GNAQ protein, human
  • Muscle Proteins
  • Intracellular Signaling Peptides and Proteins