Integrin αvβ6 mediates the effects of age-related decreases in matrix stiffness on Tenon's fibroblast activation and bleb scarring in glaucoma.

Glaucoma, including primary open-angle glaucoma (POAG) and primary angle-closure glaucoma, leads to optic nerve injury and visual field loss, often necessitating surgical intervention to lower intraocular pressure (IOP). Trabeculectomy, the most common glaucoma surgery, could fail due to excessive scarring of the filtering bleb, driven by the hyperproliferation of human Tenon's fibroblasts (HTFs). Herein, the impact of aging on matrix stiffness in Tenon's capsule tissue, the role of extracellular matrix (ECM) stiffness in the phenotypic transformation of HTFs, and the regulatory function of integrin alphavbeta6 (αvβ6) were investigated. Matrix stiffness in Tenon's capsule tissue is notably lower in elder glaucoma patients in comparison with younger ones, with reduced levels of α-SMA, collagen I, and integrin αvβ6. GFS (Glaucoma Filtration Surgery) models were established in young and old SD rats, and it was observed that older rats exhibited lower ECM stiffness, reduced fibrosis, and decreased integrin αvβ6 expression. HTFs from elderly glaucoma patients showed reduced ECM stiffness, decreased viability, impaired migration, and diminished fibrotic responses. When HTFs from young glaucoma patients were cultured on substrates of varying stiffness, it was found that stiffer substrates increased cell viability, migration, collagen synthesis, and fibrosis marker expression. Additionally, knocking down integrin αvβ6 in HTFs cultured on stiffer substrates resulted in decreased cell viability, impaired migration, reduced collagen synthesis, and lower fibrosis marker expression. In vivo knockdown of integrin αvβ6 effectively reduced ECM stiffness and fibrosis, thereby attenuating bleb scarring after GFS in young rats. Collectively, the aging-associated changes in ECM stiffness and integrin αvβ6 expression contribute to reduced fibrosis, potentially enhancing the success of trabeculectomy in elder patients.