{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:37:35Z","timestamp":1760150255150,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T00:00:00Z","timestamp":1699315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82371071","81970814","82000905","2021JSTS28"],"award-info":[{"award-number":["82371071","81970814","82000905","2021JSTS28"]}]},{"name":"clinical AFFMU foundation","award":["82371071","81970814","82000905","2021JSTS28"],"award-info":[{"award-number":["82371071","81970814","82000905","2021JSTS28"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>The outer blood\u2013retina barrier (oBRB), comprises tightly connected retinal pigment epithelium (RPE) cells, Bruch\u2019s membrane, and choroid blood vessels, and is essential for retinal health and normal visual function. Disruption of the RPE barrier and its dysfunction can lead to retinal disorders such as age-related macular degeneration (AMD). In the present study, we investigated the essential role of choroid endothelial cells (ECs) in the RPE barrier formation process and its dysfunction. We discovered that ECs promoted RPE barrier formation through angiocrine signaling. Through blocking or activating endothelial Notch signaling and conducting experiments in vitro and in vivo, we confirmed that endothelial Notch signaling regulated the expression of heparin-binding epidermal growth factor (HBEGF) and consequently impacted the expression and activity of matrix metalloproteinases (MMP)-9 in RPE cells. This modulation influenced the RPE extracellular matrix deposition, tight junctions and RPE barrier function. In in vivo experiments, the intravitreal administration of recombinant HBEGF (r-HBEGF) alleviated the RPE barrier disruption induced by subretinal injection (SI) or laser treatment and also rescued RPE barrier disruption in endothelial Notch-deficient mice. Our results showed that the endothelial Notch signaling drove HBEGF expression through angiocrine signaling and effectively improved RPE barrier function by regulating the MMP-9 expression in RPE cells. It suggests that the modulation of Notch signaling in the choroidal endothelium may offer a novel therapeutic strategy for retinal degenerative diseases.<\/jats:p>","DOI":"10.3390\/antiox12111979","type":"journal-article","created":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T11:23:39Z","timestamp":1699356219000},"page":"1979","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Endothelial Notch Signaling Regulates the Function of the Retinal Pigment Epithelial Barrier via EC Angiocrine Signaling"],"prefix":"10.3390","volume":"12","author":[{"given":"Yali","family":"Niu","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"College of Life Sciences, Northwest University, Xi\u2019an 710069, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixuan","family":"Xi","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Northwest University, Xi\u2019an 710069, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yutong","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaojia","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianhao","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianfang","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guorui","family":"Dou","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Tisi, A., Feligioni, M., Passacantando, M., Ciancaglini, M., and Maccarone, R. 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