{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T17:16:26Z","timestamp":1793121386826,"version":"4.5.0"},"posted":{"date-parts":[[2025,10,24]]},"group-title":"Cell Biology","reference-count":67,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:00:00Z","timestamp":1761264000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01EY025799"],"award-info":[{"award-number":["R01EY025799"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01EY032609"],"award-info":[{"award-number":["R01EY032609"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Dr. David L. Epstein Award"},{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"crossref","award":["M2021018N"],"award-info":[{"award-number":["M2021018N"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Northwestern University Center for Engineering in Vision and Ophthalmology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Elevated intraocular pressure (IOP), driven by increased outflow resistance in the trabecular meshwork and Schlemm\u2019s canal (SC), is a primary risk factor for glaucoma. This resistance is regulated by broadly active endothelial signaling systems such as ANGPT1-TIE2 and by dynamic flow-responsive pathways that remain poorly understood. Here, we identify a previously unrecognized, TIE2-independent, mechanosensitive ANGPT2\u2013integrin \u03b19\u03b21 pathway in the SC endothelium that regulates IOP. In vitro and in vivo, we show that activation of the mechanosensory channel PIEZO1 triggers ANGPT2 secretion and promotes cell-surface clustering of integrin \u03b19\u03b21. Deletion of SC-expressed\n                  <jats:italic>Piezo1<\/jats:italic>\n                  or\n                  <jats:italic>Itga9<\/jats:italic>\n                  in mice resulted in SC narrowing, impaired flow-mediated SC endothelial proliferation, IOP elevation and glaucoma. Furthermore, ANGPT2 deficiency or blockade disrupted PIEZO1-induced integrin activation and reduced aqueous humor outflow facility. These findings establish autocrine PIEZO1\u2013ANGPT2\u2013ITGA9 signaling as a link between mechanosensory stimuli, SC structure and IOP regulation, offering promising new targets for glaucoma therapy.\n                <\/jats:p>","DOI":"10.1101\/2025.10.24.683742","type":"posted-content","created":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T05:10:55Z","timestamp":1761369055000},"source":"Crossref","is-referenced-by-count":3,"title":["Piezo1 Triggers an Angiopoietin-2-Integrin Signaling Loop in Schlemm\u2019s Canal to Regulate Intraocular Pressure"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4613-7048","authenticated-orcid":false,"given":"Naoki","family":"Kiyota","sequence":"first","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilip K.","family":"Deb","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyuan","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology & Vision Sciences, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerolous","family":"Salama","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology & Vision Sciences, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin R.","family":"Thomson","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Department of Biomedical Engineering, Northwestern University McCormick School of Engineering, Evanston, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3706-5727","authenticated-orcid":false,"given":"Susan E.","family":"Quaggin","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026032004500700000_2025.10.24.683742v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2014.05.013"},{"key":"2026032004500700000_2025.10.24.683742v2.2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.3192"},{"key":"2026032004500700000_2025.10.24.683742v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2015.04.029"},{"key":"2026032004500700000_2025.10.24.683742v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/bs.pmbts.2015.06.007"},{"key":"2026032004500700000_2025.10.24.683742v2.5","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1001\/archopht.120.10.1268","article-title":"Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial","volume":"120","year":"2002","journal-title":"Arch. 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