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Yet, the cellular injury and mechanosensing mechanisms underlying the resulting damage have remained critically unclear. We previously identified Annexin A4 (ANXA4) from a proteomic analyses of human ONH astrocytes undergoing pathological biomechanical strain that mimics glaucomatous conditions. Annexins are a family of calcium\u2010dependent phospholipid binding proteins with key functions in plasma membrane repair (PMR); an active mechanism to limit and mend cellular injury that involves membrane and cytoskeletal reorganizations. However, a role for direct membrane damage and PMR has not been well studied in the context of biomechanical strain, such as that associated with glaucoma. Here we report that this moderate strain surprisingly damages cell membranes to increase permeability in a calcium\u2010dependent manner, and induces rapid aggregation of ANXA4 at injury sites. ANXA4 loss\u2010of\u2010function increases permeability, while exogenous ANXA4 reduces it. Furthermore, ANXA4 aggregation is associated with F\u2010actin dynamics in vitro, and remarkably this interaction and aggregation signature is also observed in the glaucomatous ONH in patient samples. Together these studies link moderate biomechanical strain with direct membrane damage and actin dynamics, and identify an active PMR role for ANXA4 in new model of cell injury associated with glaucoma pathogenesis.<\/jats:p>","DOI":"10.1002\/jcp.30834","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T15:25:39Z","timestamp":1658417139000},"page":"3687-3702","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Evidence of an Annexin\u00a0A4 mediated plasma membrane repair response to biomechanical strain associated with glaucoma pathogenesis"],"prefix":"10.1002","volume":"237","author":[{"given":"Nevena","family":"Vicic","sequence":"first","affiliation":[{"name":"Donald K Johnson Eye Institute, Krembil Research Institute University Health Network  Toronto Ontario Canada"},{"name":"Department of Ophthalmology and Vision Science University of Toronto School of Medicine  Toronto Ontario Canada"},{"name":"Department of Laboratory Medicine and Pathobiology University of Toronto School of Medicine  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxin","family":"Guo","sequence":"additional","affiliation":[{"name":"Donald K Johnson Eye Institute, Krembil Research Institute University Health Network  Toronto Ontario Canada"},{"name":"Department of Ophthalmology and Vision Science University of Toronto School of Medicine  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren","family":"Chan","sequence":"additional","affiliation":[{"name":"Donald K Johnson Eye Institute, Krembil Research Institute University Health Network  Toronto Ontario Canada"},{"name":"Department of Ophthalmology and Vision Science University of Toronto School of Medicine  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G","family":"Flanagan","sequence":"additional","affiliation":[{"name":"The Herbert Wertheim School of Optometry and Vision Science University of California Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian A.","family":"Sigal","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8776-223X","authenticated-orcid":false,"given":"Jeremy M.","family":"Sivak","sequence":"additional","affiliation":[{"name":"Donald K Johnson Eye Institute, Krembil Research Institute University Health Network  Toronto Ontario Canada"},{"name":"Department of Ophthalmology and Vision Science University of Toronto School of Medicine  Toronto Ontario Canada"},{"name":"Department of Laboratory Medicine and Pathobiology University of Toronto School of Medicine  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,21]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201011018"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2011.11.002"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2018.11.005"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.015389"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16143-6"},{"issue":"10","key":"e_1_2_6_7_1","first-page":"2991","article-title":"The optic nerve head as a biomechanical structure: Initial finite element modeling","volume":"41","author":"Bellezza A. 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