Extracellular matrix remodeling and endothelial fibrosis in Sturge-Weber syndrome secondary glaucoma: Insights from aqueous humor proteomics.

PURPOSE: Sturge‒Weber syndrome (SWS), a rare neurocutaneous disorder, frequently causes secondary glaucoma, leading to irreversible vision loss. The pathogenesis remains unclear, hindering targeted therapy development. This study investigated the molecular basis of SWS-associated glaucoma via aqueous humor (AH) proteomics and functional pathway analysis.

METHODS

Comparative proteomic profiling of AH from 6 SWS glaucoma patients and 3 cataract controls was performed. For functional validation, GNAQ p.R183Q-mutant human umbilical vein endothelial cells (HUVECs) were used: qRT‒PCR was used to assess extracellular matrix (ECM) expression, Transwell assays were used to measure endothelial permeability, and Western blotting was used to evaluate the expression of tight junction proteins and α-SMA. Morphological changes in SWS episcleral vessels were evaluated with Hematoxylin-Eosin (H&E) and Masson's staining. Immunofluorescence was used to quantify α-SMA expression in SWS episcleral veins. Statistical significance was determined by two-tailed t tests (P < 0.05).

RESULTS

Proteomics revealed abnormal upregulation of ECM proteins in SWS AH, which was confirmed by qRT‒PCR in mutant HUVECs. Mutant cells exhibited increased endothelial permeability, tight junction protein downregulation, and increased α-SMA expression, indicating endothelial barrier dysfunction and fibrosis. H&E and Masson's staining revealed dilatation malformations, thickened vessel walls, disorganized structures, and perivascular ECM deposition in SWS episcleral vessels. AH proteomics also revealed dysregulated lipid metabolism.

CONCLUSIONS

This comprehensive proteomic profile of AH implicates dysregulated ECM remodeling in the pathogenesis of SWS-glaucoma. The vascular endothelium may contribute to fibrosis through abnormal ECM secretion and impaired barrier function. On the basis of AH proteomics, this study provides a multifaceted characterization of episcleral vascular fibrosis in SWS and its potential formation mechanisms. Our findings provide insights into the pathogenesis of SWS-associated secondary glaucoma and inform targeted therapy development.