{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T07:23:23Z","timestamp":1768807403566,"version":"3.49.0"},"reference-count":19,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T00:00:00Z","timestamp":1636070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000615","name":"Fight for Sight","doi-asserted-by":"publisher","award":["Mercer Fund"],"award-info":[{"award-number":["Mercer Fund"]}],"id":[{"id":"10.13039\/501100000615","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017645","name":"Moorfields Eye Charity","doi-asserted-by":"publisher","award":["Special Trustees"],"award-info":[{"award-number":["Special Trustees"]}],"id":[{"id":"10.13039\/501100017645","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bill Brown Charitable Trust","award":["Senior Research Fellowship"],"award-info":[{"award-number":["Senior Research Fellowship"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Age-related macular degeneration (AMD) is a common blinding disease in the western world that is linked to the loss of fenestration in the choriocapillaris that sustains the retinal pigment epithelium and photoreceptors in the back of the eye. Changes in ocular and systemic zinc concentrations have been associated with AMD; therefore, we hypothesized that these changes might be directly involved in fenestrae formation. To test this hypothesis, an endothelial cell (bEND.5) model for fenestrae formation was treated with different concentrations of zinc sulfate (ZnSO4) solution for up to 20 h. Fenestrae were visualized by staining for Plasmalemmal Vesicle Associated Protein-1 (PV-1), the protein that forms the diaphragms of the fenestrated endothelium. Size and distribution were monitored by transmission electron microscopy (TEM). We found that zinc induced the redistribution of PV-1 into areas called sieve plates containing ~70-nm uniform size and typical morphology fenestrae. As AMD is associated with reduced zinc concentrations in the serum and in ocular tissues, and dietary zinc supplementation is recommended to slow disease progression, we propose here that the elevation of zinc concentration may restore choriocapillaris fenestration resulting in improved nutrient flow and clearance of waste material in the retina.<\/jats:p>","DOI":"10.3390\/ijms222111974","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T10:33:09Z","timestamp":1636108389000},"page":"11974","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Potential New Role for Zinc in Age-Related Macular Degeneration through Regulation of Endothelial Fenestration"],"prefix":"10.3390","volume":"22","author":[{"given":"Fiona","family":"Cunningham","sequence":"first","affiliation":[{"name":"Wellcome-Wolfson Institute of Experimental Medicine, Queen\u2019s University, Belfast BT9 7BL, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Cahyadi","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7467-2174","authenticated-orcid":false,"given":"Imre","family":"Lengyel","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute of Experimental Medicine, Queen\u2019s University, Belfast BT9 7BL, UK"},{"name":"UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1056\/NEJMra062326","article-title":"Age-Related Macular Degeneration","volume":"355","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.2147\/CIA.S143508","article-title":"Recent developments in age-related macular degeneration: A review","volume":"12","author":"Yassin","year":"2017","journal-title":"Clin. Interv. Aging"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3985","DOI":"10.1167\/iovs.12-11552","article-title":"A Systematic Review on Zinc for the Prevention and Treatment of Age-Related Macular Degeneration","volume":"54","author":"Vishwanathan","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Age-Related Eye Disease Study Research Group (2001). A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation with Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch. Ophthalmol., 119, 1417\u20131436.","DOI":"10.1001\/archopht.119.10.1417"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1001\/jama.294.24.3101","article-title":"Dietary Intake of Antioxidants and Risk of Age-Related Macular Degeneration","volume":"294","author":"Boekhoorn","year":"2005","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1801049","DOI":"10.1002\/mnfr.201801049","article-title":"Zinc Nutrition and Inflammation in the Aging Retina","volume":"63","author":"Gilbert","year":"2019","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Emri, E., Kortvely, E., Dammeier, S., Klose, F., Simpson, D., Consortium, E.-R., den Hollander, A.I., Ueffing, M., and Lengyel, I. (2020). A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium. Nutrients, 12.","DOI":"10.3390\/nu12103051"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1038\/eye.2009.318","article-title":"Development of the human choriocapillaris","volume":"24","author":"Lutty","year":"2010","journal-title":"Eye"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16770","DOI":"10.1073\/pnas.0603501103","article-title":"An in vitro assay reveals a role for the diaphragm protein PV-1 in endothelial fenestra morphogenesis","volume":"103","author":"Ioannidou","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1083\/jcb.100.2.418","article-title":"Endothelial fenestral diaphragms: A quick-freeze, deep-etch study","volume":"100","author":"Bearer","year":"1985","journal-title":"J. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4982","DOI":"10.1167\/iovs.09-3639","article-title":"Relationship between RPE and choriocapillaris in age-related macular degeneration","volume":"50","author":"McLeod","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"18751","DOI":"10.1073\/pnas.0905010106","article-title":"An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris","volume":"106","author":"Kurihara","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jtemb.2018.02.028","article-title":"The effects of zinc supplementation on primary human retinal pigment epithelium","volume":"49","author":"Pao","year":"2018","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Blasiak, J., Pawlowska, E., Chojnacki, J., Szczepanska, J., Chojnacki, C., and Kaarniranta, K. (2020). Zinc and Autophagy in Age-Related Macular Degeneration. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21144994"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1001\/archopht.1988.01060130202026","article-title":"Oral zinc in macular degeneration","volume":"106","author":"Newsome","year":"1988","journal-title":"Arch. Ophthalmol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1258\/ebm.2010.009258","article-title":"Free zinc ions outside a narrow concentration range are toxic to a variety of cells in vitro","volume":"235","author":"Bozym","year":"2010","journal-title":"Exp. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"L874","DOI":"10.1152\/ajplung.00328.2010","article-title":"A role for zinc in regulating hypoxia-induced contractile events in pulmonary endothelium","volume":"300","author":"Bernal","year":"2011","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1021\/acschemneuro.6b00452","article-title":"Zinc and Copper Effects on Stability of Tubulin and Actin Networks in Dendrites and Spines of Hippocampal Neurons","volume":"8","author":"Perrin","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.bbrc.2019.11.085","article-title":"Retinal VEGFA maintains the ultrastructure and function of choriocapillaris by preserving the endothelial PLVAP","volume":"522","author":"Kim","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11974\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:26:07Z","timestamp":1760167567000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,5]]},"references-count":19,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222111974"],"URL":"https:\/\/doi.org\/10.3390\/ijms222111974","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,5]]}}}