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As such, dysfunction of the RPE underlies pathology leading to development of age\u2010related macular degeneration (AMD), the leading cause of vision loss among the elderly in industrialized nations. A major responsibility of the RPE is to process photoreceptor outer segments, which relies on the proper functioning of its endocytic pathways and endosomal trafficking. Exosomes and other extracellular vesicles (EVs) from RPE are an essential part of these pathways and may be early indicators of cellular stress. To test the role of small EVs (sEVs) including exosomes, that may underlie the early stages of AMD, we used a polarized primary RPE cell culture model under chronic subtoxic oxidative stress. Unbiased proteomic analyses of highly purified basolateral sEVs from oxidatively stressed RPE cultures revealed changes in proteins involved in epithelial barrier integrity. There were also significant changes in proteins accumulating in the basal\u2010side sub\u2010RPE extracellular matrix during oxidative stress, that could be prevented with an inhibitor of sEV release. Thus, chronic subtoxic oxidative stress in primary RPE cultures induces changes in sEV content, including basal\u2010side specific desmosome and hemidesmosome shedding via sEVs. These findings provide novel biomarkers of early cellular dysfunction and opportunity for therapeutic intervention in age\u2010related retinal diseases (e.g., AMD).<\/jats:p>","DOI":"10.1002\/jex2.116","type":"journal-article","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T02:23:05Z","timestamp":1697077385000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Polarized desmosome and hemidesmosome shedding via small extracellular vesicles is an early indicator of outer blood\u2010retina barrier dysfunction"],"prefix":"10.1002","volume":"2","author":[{"given":"Belinda J.","family":"Hernandez","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Duke Eye Center Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolai P.","family":"Skiba","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Duke Eye Center Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Pl\u00f6ssl","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University of Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Strain","sequence":"additional","affiliation":[{"name":"Duke Molecular Physiology Institute, Department of Medicine Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy Augusta University  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Grigsby","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Duke Eye Center Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Una","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Duke Eye Center Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha A.","family":"Cady","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Duke Eye Center Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikram","family":"Manocha","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Duke Eye Center Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvydas","family":"Maminishkis","sequence":"additional","affiliation":[{"name":"Ophthalmic Genetics and Visual Function Branch, Section on Epithelial and Retinal Physiology and Disease National Eye Institute, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"TeddiJo","family":"Watkins","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Duke Eye Center Duke University  Durham North Carolina USA"},{"name":"Office of Animal Welfare Assurance, Duke Animal Care and Use Program Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheldon S.","family":"Miller","sequence":"additional","affiliation":[{"name":"Ophthalmic Genetics and Visual Function Branch, Section on Epithelial and Retinal Physiology and Disease National Eye Institute, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Ashley\u2010Koch","sequence":"additional","affiliation":[{"name":"Duke Molecular Physiology Institute, Department of Medicine Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Daniel","family":"Stamer","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Duke Eye Center Duke University  Durham North Carolina USA"},{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard H. F.","family":"Weber","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University of Regensburg  Regensburg Germany"},{"name":"Institute of Clinical Human Genetics University Hospital Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Bowes Rickman","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Duke Eye Center Duke University  Durham North Carolina USA"},{"name":"Department of Cell Biology Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2907-0371","authenticated-orcid":false,"given":"Mikael","family":"Klingeborn","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Duke Eye Center Duke University  Durham North Carolina USA"},{"name":"McLaughlin Research Institute  Great Falls Montana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,11]]},"reference":[{"issue":"6","key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.exer.2007.08.010","article-title":"VEGF modulation of retinal pigment epithelium resistance","volume":"85","author":"Ablonczy Z.","year":"2007","journal-title":"Experimental Eye Research"},{"issue":"12","key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"8614","DOI":"10.1167\/iovs.11-8021","article-title":"Human retinal pigment epithelium cells as functional models for the RPE in vivo","volume":"52","author":"Ablonczy Z.","year":"2011","journal-title":"Investigative Ophthalmology & Visual Science"},{"issue":"44","key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"30177","DOI":"10.1074\/jbc.M109.032391","article-title":"Pigment epithelium\u2010derived factor maintains retinal pigment epithelium function by inhibiting vascular endothelial growth factor\u2010R2 signaling through gamma\u2010secretase","volume":"284","author":"Ablonczy Z.","year":"2009","journal-title":"The Journal of Biological Chemistry"},{"issue":"10","key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1001\/archopht.119.10.1417","article-title":"A randomized, placebo\u2010controlled, clinical trial of high\u2010dose supplementation with vitamins C and E, beta carotene, and zinc for age\u2010related macular degeneration and vision loss: AREDS report no. 8","volume":"119","author":"Age\u2010Related Eye Disease Study Research Group","year":"2001","journal-title":"Archives of Ophthalmology (Chicago, Ill.: 1960)"},{"issue":"11","key":"e_1_2_9_6_1","first-page":"2706","article-title":"Downregulation of differentiation specific gene expression by oxidative stress in ARPE\u201019 cells","volume":"42","author":"Alizadeh M.","year":"2001","journal-title":"Investigative Ophthalmology & Visual Science"},{"issue":"6","key":"e_1_2_9_7_1","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/S0002-9394(00)00961-2","article-title":"Local cellular sources of apolipoprotein E in the human retina and retinal pigmented epithelium: Implications for the process of drusen formation","volume":"131","author":"Anderson D. 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