Transient receptor potential vanilloid 4 modulates substrate stiffness mechanosensing and transcellular pore formation in human Schlemm’s canal cells
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Pathological changes in the biomechanical environment of Schlemm’s canal (SC) inner wall cells, such as substrate stiffening and increased cellular stretch, are associated with ocular hypertension, a key risk factor for the development of glaucoma. Cell membrane stretch can trigger the activation of transient receptor potential vanilloid 4 (TRPV4) mechanosensitive ion channels, allowing calcium influx and initiating downstream signaling. However, the precise role of TRPV4 in SC cell mechanobiology remains unclear. Here, we demonstrate that sustained inhibition of TRPV4 activity modulates substrate stiffness mechanosensing to thereby affect the remodeling of the actin cytoskeleton and extracellular matrix of SC cells. This is accompanied by a reduction in cell stiffness and an increase in transcellular pore forming ability, potentially lowering outflow resistance and risk of ocular hypertension. Interestingly, acute activation of TRPV4 channels induces Ca2+ influx, increasing transcellular pore formation in SC cells. Notably, reduced TRPV4 mechanosensing is observed in glaucomatous SC cells, resulting in reduced transcellular pore forming ability. These findings suggest novel potential strategies based on targeting TRPV4 in SC cells for the treatment of ocular hypertension in glaucoma.
Date Issued
2025-10-15
Date Acceptance
2025-09-26
Citation
Acta Biomaterialia, 2025, 206, pp.110-124
ISSN
1742-7061
Publisher
Elsevier BV
Start Page
110
End Page
124
Journal / Book Title
Acta Biomaterialia
Volume
206
Copyright Statement
© 2025 The Authors. Published by Elsevier Inc. on behalf of Acta Materialia Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41022289
PII: S1742-7061(25)00706-8
Subjects
Calcium signaling
ECM stiffening
Glaucoma
Hydrogel
Ion channel
Mechanobiology
Tissue engineering
Transcellular pore
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2025-09-27