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Editors Selection IGR 21-4

Comment

Comment by Heather McGowan & Louis Pasquale on:

92713 Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma, Patel PD; Chen YL; Kasetti RB et al., Proceedings of the National Academy of Sciences of the United States of America, 2021; 118:

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Nitric Oxide (NO) is a gasomitter implicated in regulating multiple essential biological processes, including intraocular pressure (IOP). In this study, the authors demonstrate a link between shear stress-mediated transient receptor potential vanilloid 4 (TRPV4) activation and NO-mediated IOP reduction.

Using a combination of high-speed calcium imaging and patch clamp, the authors successfully demonstrated the presence of functional TRPV4 in human trabecular meshwork (TM) cells. Furthermore, they demonstrated up-regulation of nitric oxide synthase 3 (NOS3) phosphorylation and NO production in human TM cells following treatment with a TRPV4 agonist. They then provided further evidence for this functional relationship by demonstrating that NOS3 knockout in mice eliminates TRPV4-mediated IOP reduction. Finally, using sophisticated methods, they demonstrated that shear stress-mediated TRPV4 activity and TRPV4-induced NO production was reduced in glaucomatous human TM cells, despite a slightly increased number of TRPV4 receptors, indicating that TRPV4 receptor dysfunction may contribute to elevated IOP in glaucoma.

This elegant paper elucidates an important functional link between shear stress related TRPV4 activation, NO production, and subsequent lowering of IOP

This elegant paper elucidates an important functional link between shear stress related TRPV4 activation, NO production, and subsequent lowering of IOP, as well as the implications of TRPV4 dysfunction for the possible development of glaucoma. While the paper certainly makes a strong case for the importance of TRPV4 function in IOP homeostasis, multiple pathways involving other mechano-sensing receptors (e.g., Caveolin-1, VEGFR/ VE-cadherin/PECAM-1) also exist in the TM and converge on the NO pathway. Furthermore, two of seven donors of glaucoma TM cells were very old (96 and 99 years of age), and it is unknown whether any of the eyes from which TM cells were harvested had laser trabeculoplasty or glaucoma surgery. More analysis of glaucoma eyes with a defined past ocular history would be worthwhile. Additional studies exploring if TRPV4 gene variants are associated with increased IOP or glaucoma risk will be interesting.

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