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Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma

Primary Open Angle Glaucoma (POAG) is the most common form of glaucoma that leads to irreversible vision loss. Dysfunction of trabecular meshwork (TM) tissue, a major regulator of aqueous humor (AH) outflow resistance, is associated with intraocular pressure (IOP) elevation in POAG. However, the und...

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Autores principales: Patel, Pinkal D., Chen, Yen-Lin, Kasetti, Ramesh B., Maddineni, Prabhavathi, Mayhew, William, Millar, J. Cameron, Ellis, Dorette Z., Sonkusare, Swapnil K., Zode, Gulab S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072326/
https://www.ncbi.nlm.nih.gov/pubmed/33853948
http://dx.doi.org/10.1073/pnas.2022461118
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author Patel, Pinkal D.
Chen, Yen-Lin
Kasetti, Ramesh B.
Maddineni, Prabhavathi
Mayhew, William
Millar, J. Cameron
Ellis, Dorette Z.
Sonkusare, Swapnil K.
Zode, Gulab S.
author_facet Patel, Pinkal D.
Chen, Yen-Lin
Kasetti, Ramesh B.
Maddineni, Prabhavathi
Mayhew, William
Millar, J. Cameron
Ellis, Dorette Z.
Sonkusare, Swapnil K.
Zode, Gulab S.
author_sort Patel, Pinkal D.
collection PubMed
description Primary Open Angle Glaucoma (POAG) is the most common form of glaucoma that leads to irreversible vision loss. Dysfunction of trabecular meshwork (TM) tissue, a major regulator of aqueous humor (AH) outflow resistance, is associated with intraocular pressure (IOP) elevation in POAG. However, the underlying pathological mechanisms of TM dysfunction in POAG remain elusive. In this regard, transient receptor potential vanilloid 4 (TRPV4) cation channels are known to be important Ca(2+) entry pathways in multiple cell types. Here, we provide direct evidence supporting Ca(2+) entry through TRPV4 channels in human TM cells and show that TRPV4 channels in TM cells can be activated by increased fluid flow/shear stress. TM-specific TRPV4 channel knockout in mice elevated IOP, supporting a crucial role for TRPV4 channels in IOP regulation. Pharmacological activation of TRPV4 channels in mouse eyes also improved AH outflow facility and lowered IOP. Importantly, TRPV4 channels activated endothelial nitric oxide synthase (eNOS) in TM cells, and loss of eNOS abrogated TRPV4-induced lowering of IOP. Remarkably, TRPV4-eNOS signaling was significantly more pronounced in TM cells compared to Schlemm’s canal cells. Furthermore, glaucomatous human TM cells show impaired activity of TRPV4 channels and disrupted TRPV4-eNOS signaling. Flow/shear stress activation of TRPV4 channels and subsequent NO release were also impaired in glaucomatous primary human TM cells. Together, our studies demonstrate a central role for TRPV4-eNOS signaling in IOP regulation. Our results also provide evidence that impaired TRPV4 channel activity in TM cells contributes to TM dysfunction and elevated IOP in glaucoma.
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spelling pubmed-80723262021-05-10 Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma Patel, Pinkal D. Chen, Yen-Lin Kasetti, Ramesh B. Maddineni, Prabhavathi Mayhew, William Millar, J. Cameron Ellis, Dorette Z. Sonkusare, Swapnil K. Zode, Gulab S. Proc Natl Acad Sci U S A Biological Sciences Primary Open Angle Glaucoma (POAG) is the most common form of glaucoma that leads to irreversible vision loss. Dysfunction of trabecular meshwork (TM) tissue, a major regulator of aqueous humor (AH) outflow resistance, is associated with intraocular pressure (IOP) elevation in POAG. However, the underlying pathological mechanisms of TM dysfunction in POAG remain elusive. In this regard, transient receptor potential vanilloid 4 (TRPV4) cation channels are known to be important Ca(2+) entry pathways in multiple cell types. Here, we provide direct evidence supporting Ca(2+) entry through TRPV4 channels in human TM cells and show that TRPV4 channels in TM cells can be activated by increased fluid flow/shear stress. TM-specific TRPV4 channel knockout in mice elevated IOP, supporting a crucial role for TRPV4 channels in IOP regulation. Pharmacological activation of TRPV4 channels in mouse eyes also improved AH outflow facility and lowered IOP. Importantly, TRPV4 channels activated endothelial nitric oxide synthase (eNOS) in TM cells, and loss of eNOS abrogated TRPV4-induced lowering of IOP. Remarkably, TRPV4-eNOS signaling was significantly more pronounced in TM cells compared to Schlemm’s canal cells. Furthermore, glaucomatous human TM cells show impaired activity of TRPV4 channels and disrupted TRPV4-eNOS signaling. Flow/shear stress activation of TRPV4 channels and subsequent NO release were also impaired in glaucomatous primary human TM cells. Together, our studies demonstrate a central role for TRPV4-eNOS signaling in IOP regulation. Our results also provide evidence that impaired TRPV4 channel activity in TM cells contributes to TM dysfunction and elevated IOP in glaucoma. National Academy of Sciences 2021-04-20 2021-04-14 /pmc/articles/PMC8072326/ /pubmed/33853948 http://dx.doi.org/10.1073/pnas.2022461118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Patel, Pinkal D.
Chen, Yen-Lin
Kasetti, Ramesh B.
Maddineni, Prabhavathi
Mayhew, William
Millar, J. Cameron
Ellis, Dorette Z.
Sonkusare, Swapnil K.
Zode, Gulab S.
Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma
title Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma
title_full Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma
title_fullStr Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma
title_full_unstemmed Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma
title_short Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma
title_sort impaired trpv4-enos signaling in trabecular meshwork elevates intraocular pressure in glaucoma
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072326/
https://www.ncbi.nlm.nih.gov/pubmed/33853948
http://dx.doi.org/10.1073/pnas.2022461118
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