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Targeting YAP mechanosignaling to ameliorate stiffness-induced Schlemm’s canal cell pathobiology
Pathologic alterations in the biomechanical properties of the Schlemm’s canal (SC) inner wall endothelium and its immediate vicinity are strongly associated with ocular hypertension in glaucoma due to decreased outflow facility. Specifically, the underlying trabecular meshwork is substantially stiff...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541092/ https://www.ncbi.nlm.nih.gov/pubmed/37781615 http://dx.doi.org/10.1101/2023.09.08.556840 |
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author | Li, Haiyan Kuhn, Megan Kelly, Ruth A. Singh, Ayushi Palanivel, Kavipriya Kovai Salama, Izzy De Ieso, Michael L. Stamer, W. Daniel Ganapathy, Preethi S. Herberg, Samuel |
author_facet | Li, Haiyan Kuhn, Megan Kelly, Ruth A. Singh, Ayushi Palanivel, Kavipriya Kovai Salama, Izzy De Ieso, Michael L. Stamer, W. Daniel Ganapathy, Preethi S. Herberg, Samuel |
author_sort | Li, Haiyan |
collection | PubMed |
description | Pathologic alterations in the biomechanical properties of the Schlemm’s canal (SC) inner wall endothelium and its immediate vicinity are strongly associated with ocular hypertension in glaucoma due to decreased outflow facility. Specifically, the underlying trabecular meshwork is substantially stiffer in glaucomatous eyes compared to that from normal eyes. This raises the possibility of a critical involvement of mechanotransduction processes in driving SC cell dysfunction. Yes-associated protein (YAP) has emerged as a key contributor to glaucoma pathogenesis. However, the molecular underpinnings of SC cell YAP mechanosignaling in response to glaucomatous extracellular matrix (ECM) stiffening are not well understood. Using a novel biopolymer hydrogel that facilitates dynamic and reversible stiffness tuning, we investigated how ECM stiffening modulates YAP activity in primary human SC cells, and whether disruption of YAP mechanosignaling attenuates SC cell pathobiology and increases ex vivo outflow facility. We demonstrated that ECM stiffening drives pathologic YAP activation and cytoskeletal reorganization in SC cells, which was fully reversible by matrix softening in a distinct time-dependent manner. Furthermore, we showed that pharmacologic or genetic disruption of YAP mechanosignaling abrogates stiffness-induced SC cell dysfunction involving altered cytoskeletal and ECM remodeling. Lastly, we found that perfusion of the clinically-used, small molecule YAP inhibitor verteporfin (without light activation) increases ex vivo outflow facility in normal mouse eyes. Collectively, our data provide new evidence for a pathologic role of aberrant YAP mechanosignaling in SC cell dysfunction and suggest that YAP inhibition has therapeutic value for treating ocular hypertension in glaucoma. |
format | Online Article Text |
id | pubmed-10541092 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-105410922023-10-01 Targeting YAP mechanosignaling to ameliorate stiffness-induced Schlemm’s canal cell pathobiology Li, Haiyan Kuhn, Megan Kelly, Ruth A. Singh, Ayushi Palanivel, Kavipriya Kovai Salama, Izzy De Ieso, Michael L. Stamer, W. Daniel Ganapathy, Preethi S. Herberg, Samuel bioRxiv Article Pathologic alterations in the biomechanical properties of the Schlemm’s canal (SC) inner wall endothelium and its immediate vicinity are strongly associated with ocular hypertension in glaucoma due to decreased outflow facility. Specifically, the underlying trabecular meshwork is substantially stiffer in glaucomatous eyes compared to that from normal eyes. This raises the possibility of a critical involvement of mechanotransduction processes in driving SC cell dysfunction. Yes-associated protein (YAP) has emerged as a key contributor to glaucoma pathogenesis. However, the molecular underpinnings of SC cell YAP mechanosignaling in response to glaucomatous extracellular matrix (ECM) stiffening are not well understood. Using a novel biopolymer hydrogel that facilitates dynamic and reversible stiffness tuning, we investigated how ECM stiffening modulates YAP activity in primary human SC cells, and whether disruption of YAP mechanosignaling attenuates SC cell pathobiology and increases ex vivo outflow facility. We demonstrated that ECM stiffening drives pathologic YAP activation and cytoskeletal reorganization in SC cells, which was fully reversible by matrix softening in a distinct time-dependent manner. Furthermore, we showed that pharmacologic or genetic disruption of YAP mechanosignaling abrogates stiffness-induced SC cell dysfunction involving altered cytoskeletal and ECM remodeling. Lastly, we found that perfusion of the clinically-used, small molecule YAP inhibitor verteporfin (without light activation) increases ex vivo outflow facility in normal mouse eyes. Collectively, our data provide new evidence for a pathologic role of aberrant YAP mechanosignaling in SC cell dysfunction and suggest that YAP inhibition has therapeutic value for treating ocular hypertension in glaucoma. Cold Spring Harbor Laboratory 2023-09-09 /pmc/articles/PMC10541092/ /pubmed/37781615 http://dx.doi.org/10.1101/2023.09.08.556840 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Li, Haiyan Kuhn, Megan Kelly, Ruth A. Singh, Ayushi Palanivel, Kavipriya Kovai Salama, Izzy De Ieso, Michael L. Stamer, W. Daniel Ganapathy, Preethi S. Herberg, Samuel Targeting YAP mechanosignaling to ameliorate stiffness-induced Schlemm’s canal cell pathobiology |
title | Targeting YAP mechanosignaling to ameliorate stiffness-induced Schlemm’s canal cell pathobiology |
title_full | Targeting YAP mechanosignaling to ameliorate stiffness-induced Schlemm’s canal cell pathobiology |
title_fullStr | Targeting YAP mechanosignaling to ameliorate stiffness-induced Schlemm’s canal cell pathobiology |
title_full_unstemmed | Targeting YAP mechanosignaling to ameliorate stiffness-induced Schlemm’s canal cell pathobiology |
title_short | Targeting YAP mechanosignaling to ameliorate stiffness-induced Schlemm’s canal cell pathobiology |
title_sort | targeting yap mechanosignaling to ameliorate stiffness-induced schlemm’s canal cell pathobiology |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541092/ https://www.ncbi.nlm.nih.gov/pubmed/37781615 http://dx.doi.org/10.1101/2023.09.08.556840 |
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