{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T23:52:34Z","timestamp":1768089154867,"version":"3.49.0"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T00:00:00Z","timestamp":1634774400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K16946"],"award-info":[{"award-number":["18K16946"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Trabecular meshwork constitutes the conventional outflow pathway and controls intraocular pressure by regulating aqueous outflow. Mechanical stimulation has been studied as one of the triggers to regulate aqueous outflow in trabecular meshwork, but it is not well understood. We investigated that how transient receptor potential cation channel subfamily V member 4 (TRPV4) functions in human trabecular meshwork cells (HTMC) and affects intraocular pressure (IOP). HTMC were treated with TRPV4 siRNA, followed by incubation for 24 hours. We confirmed the suppression of <jats:italic>TRPV4<\/jats:italic> mRNA expression and the reduction of Ca<jats:sup>2+<\/jats:sup> influx by the TRPV4 agonist GSK1016790A in TRPV4 siRNA-treated HTMC. TRPV4 siRNA-treated HTMC exhibited a significant reduction in Ca<jats:sup>2+<\/jats:sup> influx and production of arachidonic acid and prostaglandin (PG) E<jats:sub>2<\/jats:sub> induced by mechanical stretch, and direct activation of TRPV4 by GSK1016790A increased production of arachidonic acid, PGE<jats:sub>2<\/jats:sub>, and PGD<jats:sub>2<\/jats:sub> and inhibited gel contraction. Furthermore, TRPV4-deficient mice had higher IOP than wild-type mice, and GSK1016790A administration lowered IOP. These results suggest that TRPV4 mediates the cellular response induced by trabecular meshwork stretch, leading to IOP reduction through the production of prostaglandins and inhibition of cell contraction. Targeting TRPV4 may have therapeutic benefits that lead to lowering IOP in glaucoma patients.<\/jats:p>","DOI":"10.1371\/journal.pone.0258911","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T17:40:17Z","timestamp":1634838017000},"page":"e0258911","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":33,"title":["TRPV4 is activated by mechanical stimulation to induce prostaglandins release in trabecular meshwork, lowering intraocular pressure"],"prefix":"10.1371","volume":"16","author":[{"given":"Takatoshi","family":"Uchida","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shota","family":"Shimizu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reiko","family":"Yamagishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzumi M.","family":"Tokuoka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiro","family":"Kita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rei","family":"Sakata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megumi","family":"Honjo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Aihara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,10,21]]},"reference":[{"key":"pone.0258911.ref001","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1136\/bjo.2005.081224","article-title":"The Number of People with Glaucoma Worldwide in 2010 and 2020","volume":"90","author":"HA Quigley","year":"2006","journal-title":"Br J Ophthalmol"},{"key":"pone.0258911.ref002","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/S0002-9394(98)00272-4","article-title":"The Effectiveness of Intraocular Pressure Reduction in the Treatment of Normal-Tension Glaucoma","volume":"126","author":"Collaborative Normal-Tension Glaucoma Study Group","year":"1998","journal-title":"Am J Ophthalmol"},{"key":"pone.0258911.ref003","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S0002-9394(00)00538-9","article-title":"The Advanced Glaucoma Intervention Study (AGIS): 7. The Relationship Between Control of Intraocular Pressure and Visual Field deterioration","volume":"130","author":"The AGIS Investigators","year":"2000","journal-title":"Am J Ophthalmol"},{"key":"pone.0258911.ref004","doi-asserted-by":"crossref","first-page":"e1001912","DOI":"10.1371\/journal.pbio.1001912","article-title":"Schlemm\u2019s Canal Is a Unique Vessel With a Combination of Blood Vascular and Lymphatic Phenotypes That Forms by a Novel Developmental Process","volume":"12","author":"K Kizhatil","year":"2014","journal-title":"PLoS Biol"},{"key":"pone.0258911.ref005","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1089\/jop.2013.0185","article-title":"Intraocular Pressure Homeostasis: Maintaining Balance in a High-Pressure Environment","volume":"30","author":"TS Acott","year":"2014","journal-title":"J Ocul Pharmacol Ther"},{"key":"pone.0258911.ref006","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1001\/archopht.1969.00990020633011","article-title":"Direct-recorded Intraocular Pressure Variations in a Human Subject","volume":"82","author":"DJ Coleman","year":"1969","journal-title":"Arch Ophthalmol"},{"key":"pone.0258911.ref007","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/0002-9394(77)90857-1","article-title":"Light Microscopic Quantitation of the Endothelial Vacuoles in Schlemm\u2019s Canal","volume":"84","author":"I Grierson","year":"1977","journal-title":"Am J Ophthalmol"},{"key":"pone.0258911.ref008","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/0014-4835(75)90218-3","article-title":"The Fine Structure of the Trabecular Meshwork at Graded Levels of Intraocular Pressure. (1) Pressure Effects within the Near-Physiological Range (8\u201330 mmHg)","volume":"20","author":"I Grierson","year":"1975","journal-title":"Exp Eye Res"},{"key":"pone.0258911.ref009","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.biocel.2016.07.012","article-title":"Modulation of TRPV4 by Diverse Mechanisms","volume":"78","author":"WG Darby","year":"2016","journal-title":"Int J Biochem Cell Biol"},{"key":"pone.0258911.ref010","doi-asserted-by":"crossref","first-page":"12871","DOI":"10.1073\/pnas.1323292111","article-title":"Primary Cilia Signaling Mediates Intraocular Pressure Sensation","volume":"111","author":"N Luo","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0258911.ref011","doi-asserted-by":"crossref","first-page":"3885","DOI":"10.1073\/pnas.1515895113","article-title":"Differential Volume Regulation and Calcium Signaling in Two Ciliary Body Cell Types is Subserved by TRPV4 Channels","volume":"113","author":"AO Jo","year":"2016","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0258911.ref012","doi-asserted-by":"crossref","first-page":"30583","DOI":"10.1038\/srep30583","article-title":"TRPV4 Regulates Calcium Homeostasis, Cytoskeletal Remodeling, Conventional Outflow and Intraocular Pressure in the Mammalian Eye","volume":"6","author":"DA Ryskamp","year":"2016","journal-title":"Sci Rep"},{"key":"pone.0258911.ref013","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2022461118","article-title":"Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma","volume":"118","author":"PD Patel","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0258911.ref014","doi-asserted-by":"crossref","first-page":"174","DOI":"10.2741\/2057","article-title":"Mechanotransduction in skeletal muscle","volume":"12","author":"TJ Burkholder","year":"2007","journal-title":"Front Biosci"},{"key":"pone.0258911.ref015","doi-asserted-by":"crossref","first-page":"59","DOI":"10.4331\/wjbc.v2.i4.59","article-title":"Shuffling the cards in signal transduction: Calcium, arachidonic acid and mechanosensitivity","volume":"2","author":"L Munaron","year":"2011","journal-title":"World J Biol Chem"},{"key":"pone.0258911.ref016","doi-asserted-by":"crossref","first-page":"4044","DOI":"10.1038\/s41598-021-83713-z","article-title":"Mechanical stretch induces Ca2+ Influx and extracellular release of PGE2 through Piezo1 activation in trabecular meshwork cells","volume":"17","author":"T Uchida","year":"2021","journal-title":"Sci Rep"},{"key":"pone.0258911.ref017","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3109\/13816810.2016.1164193","article-title":"Prostaglandins in the Eye: Function, Expression, and Roles in Glaucoma","volume":"38","author":"LP Doucette","year":"2017","journal-title":"Ophthalmic Genet"},{"key":"pone.0258911.ref018","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1111\/bph.14328","article-title":"Prostaglandin Analogues and Nitric Oxide Contribution in the Treatment of Ocular Hypertension and Glaucoma","volume":"176","author":"F Impagnatiello","year":"2019","journal-title":"Br J Pharmacol"},{"key":"pone.0258911.ref019","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1089\/jop.2013.0194","article-title":"Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma","volume":"30","author":"PV Rao","year":"2014","journal-title":"J Ocul Pharmacol Ther"},{"key":"pone.0258911.ref020","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1167\/iovs.03-0960","article-title":"Role of Lysophospholipid Growth Factors in the Modulation of Aqueous Humor Outflow Facility","volume":"45","author":"PS Mettu","year":"2004","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pone.0258911.ref021","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1016\/j.exer.2009.08.008","article-title":"Sphingosine-1-phosphate Effects on the Inner Wall of Schlemm\u2019s Canal and Outflow Facility in Perfused Human Eyes","volume":"89","author":"WD Stamer","year":"2009","journal-title":"Exp Eye Res"},{"key":"pone.0258911.ref022","doi-asserted-by":"crossref","first-page":"S107","DOI":"10.1016\/j.survophthal.2008.08.010","article-title":"Update on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction","volume":"53","author":"CB Toris","year":"2008","journal-title":"Surv Ophthalmol"},{"key":"pone.0258911.ref023","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ajo.2020.06.003","article-title":"Omidenepag Isopropyl Versus Latanoprost in Primary Open-angle Glaucoma and Ocular Hypertension: ThePhase 3 AYAME Study","volume":"220","author":"M Aihara","year":"2020","journal-title":"Am J Ophthalmol"},{"key":"pone.0258911.ref024","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jchromb.2015.05.015","article-title":"A comprehensive quantification method for eicosanoids and related compounds by using liquid chromatography\/mass spectrometry with high speed continuous ionization polarity switching","volume":"995\u2013996","author":"M Yamada","year":"2015","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"pone.0258911.ref025","doi-asserted-by":"crossref","first-page":"22664","DOI":"10.1074\/jbc.M302561200","article-title":"Impaired Pressure Sensation in Mice Lacking TRPV4","volume":"278","author":"M Suzuki","year":"2003","journal-title":"J Biol Chem"},{"key":"pone.0258911.ref026","doi-asserted-by":"crossref","first-page":"C96","DOI":"10.1152\/ajpcell.00559.2002","article-title":"Impaired Osmotic Sensation in Mice Lacking TRPV4","volume":"285","author":"A Mizuno","year":"2003","journal-title":"Am J Physiol Cell Physiol"},{"key":"pone.0258911.ref027","first-page":"146","article-title":"Reduction of intraocular pressure in mouse eyes treated with latanoprost","volume":"43","author":"M Aihara","year":"2002","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pone.0258911.ref028","doi-asserted-by":"crossref","first-page":"3028","DOI":"10.1002\/art.24799","article-title":"Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes","volume":"60","author":"MN Phan","year":"2009","journal-title":"Arthritis Rheum"},{"key":"pone.0258911.ref029","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.immuni.2018.04.021","article-title":"TRPV4 Channel Signaling in Macrophages Promotes Gastrointestinal Motility via Direct Effects on Smooth Muscle Cells","volume":"49","author":"J Luo","year":"2018","journal-title":"Immunity"},{"key":"pone.0258911.ref030","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1161\/HYPERTENSIONAHA.117.09767","article-title":"TRPV4 (Transient Receptor Potential Vanilloid 4) Mediates Endothelium-Dependent Contractions in the Aortas of Hypertensive Mice","volume":"71","author":"P Zhang","year":"2018","journal-title":"Hypertension"},{"key":"pone.0258911.ref031","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1167\/iovs.08-2800","article-title":"Effects of prostanoid EP agonists on mouse intraocular pressure","volume":"50","author":"T Saeki","year":"2009","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pone.0258911.ref032","doi-asserted-by":"crossref","first-page":"3320","DOI":"10.1167\/iovs.08-3031","article-title":"Prostanoid EP4 receptor stimulation produces ocular hypotension by a mechanism that does not appear to involve uveoscleral outflow","volume":"50","author":"DF Woodward","year":"2009","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pone.0258911.ref033","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.exer.2009.05.002","article-title":"Ocular pharmacokinetics and hypotensive activity of PF-04475270, an EP4 prostaglandin agonist in preclinical models","volume":"89","author":"G Prasanna","year":"2009","journal-title":"Exp Eye Res"},{"key":"pone.0258911.ref034","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1016\/S0968-0896(02)00016-0","article-title":"3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents","volume":"10","author":"MR Hellberg","year":"2002","journal-title":"Bioorg Med Chem"},{"key":"pone.0258911.ref035","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/jop.2008.0089","article-title":"Prostaglandin Subtype-Selective and Non-Selective IOP-Lowering Comparison in Monkeys","volume":"25","author":"BT Gabelt","year":"2009","journal-title":"J Ocul Pharmacol Ther"},{"key":"pone.0258911.ref036","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1089\/jop.2006.22.86","article-title":"Effects of a prostaglandin DP receptor agonist, AL-6598, on aqueous humor dynamics in a nonhuman primate model of glaucoma","volume":"22","author":"CB Toris","year":"2006","journal-title":"J Ocul Pharmacol Ther"},{"key":"pone.0258911.ref037","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/nature01807","article-title":"Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels","volume":"424","author":"H Watanabe","year":"2003","journal-title":"Nature"},{"key":"pone.0258911.ref038","doi-asserted-by":"crossref","first-page":"16565","DOI":"10.1074\/jbc.M113.528638","article-title":"Functional role for Piezo1 in stretch-evoked Ca2+ influx and ATP release in urothelial cell cultures","volume":"289","author":"T Miyamoto","year":"2014","journal-title":"J Biol Chem"},{"key":"pone.0258911.ref039","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.survophthal.2017.06.007","article-title":"Aging and ocular tissue stiffness in glaucoma","volume":"63","author":"B Liu","year":"2018","journal-title":"Surv Ophthalmol"},{"key":"pone.0258911.ref040","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.plefa.2004.03.021","article-title":"Prostaglandin E2 receptor subtypes, EP1, EP2, EP3 and EP4 in human and mouse ocular tissues\u2014a comparative immunohistochemical study","volume":"71","author":"S Biswas","year":"2004","journal-title":"Prostaglandins Leukot Essent Fatty Acids"},{"key":"pone.0258911.ref041","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1167\/iovs.04-1527","article-title":"Prostaglandin analogues and mouse intraocular pressure: effects of tafluprost, latanoprost, travoprost, and unoprostone, considering 24-hour variation","volume":"46","author":"T Ota","year":"2005","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pone.0258911.ref042","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1002\/jcp.24524","article-title":"Regulation of plasticity and fibrogenic activity of trabecular meshwork cells by Rho GTPase signaling","volume":"229","author":"PP Pattabiraman","year":"2014","journal-title":"J Cell Physiol"},{"key":"pone.0258911.ref043","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S1350-9462(99)00015-4","article-title":"The regulation of trabecular meshwork and ciliary muscle contractility","volume":"19","author":"M Wiederholt","year":"2000","journal-title":"Prog Retin Eye Res"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0258911","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T17:40:48Z","timestamp":1634838048000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0258911"}},"subtitle":[],"editor":[{"given":"Alexander G","family":"Obukhov","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,10,21]]},"references-count":43,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10,21]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0258911","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,21]]}}}