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Retinal pigment epithelium-derived extracellular vesicles mediate outer blood retinal barrier disruption in response to AMD-related stress

2025-12Artigo científico Acesso aberto
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dc.contributor.authorMartins, Beatriz
dc.contributor.authorBoia, Raquel
dc.contributor.authorCorreia, Diana
dc.contributor.authorRibeiro-Rodrigues, Teresa
dc.contributor.authorRamalho, José
dc.contributor.authorAmbrósio, António Francisco
dc.contributor.authorGirão, Henrique
dc.contributor.authorFernandes, Rosa
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutioniNOVA4Health - pólo NMS
dc.contributor.pblSignal Transduction Society
dc.date.accessioned2026-01-14T15:56:34Z
dc.date.available2026-01-14T15:56:34Z
dc.date.issued2025-12
dc.descriptionPublisher Copyright: © The Author(s) 2025.
dc.description.abstractBackground: Age-related macular degeneration (AMD) is a leading cause of vision loss among the elderly, primarily affecting the central vision. This progressive degenerative disease is characterized by the dysregulation and degeneration of the retinal pigment epithelium (RPE), a crucial cell layer beneath the photoreceptors that maintains outer retinal homeostasis. Emerging evidence suggests that during AMD, stressed RPE cells release extracellular vesicles (EVs) carrying bioactive cargo, which may compromise the outer blood-retinal barrier (oBRB) and accelerate disease progression. This study explores the role of EVs released by RPE cells under pro-inflammatory conditions in disrupting retinal integrity. Methods: Highly polarized primary cultures of porcine RPE (pRPE) and porcine eyecups with the RPE exposed were treated with tumor necrosis factor (TNF), lipopolysaccharide (LPS), or EVs derived from inflamed RPE cells. Additionally, Balb/c mice were intravitreally injected with RPE-derived EVs. Results: We show that EVs secreted by the apical membrane domain of porcine RPE cells exposed to LPS or TNF impair the RPE monolayer in polarized cultures, disrupt the oBRB in ex vivo porcine eyecups, and induce retinal structural damage detected in vivo in Balb/c mice. Intravitreal injection of LPS-derived EVs triggers photoreceptor and RPE layers thinning, increases reactivity in astrocytes and Müller cells, promotes pro-inflammatory microglial activation and recruitment, particularly into the outer retina, and elevates retinal apoptosis. Mechanistically, matrix metalloproteinases (MMPs) activity mediates EV-induced RPE monolayer disruption, whereas MMPs activity inhibition mitigates these effects. Conclusion: Our findings reveal a novel EV-driven mechanism contributing to retinal degeneration progression, highlighting inflammation-derived apical EVs as key players in diseases involving oBRB dysfunction. Targeting EV-mediated signaling and MMPs activity may offer therapeutic strategies for preserving retinal structure and function in inflammatory retinal diseases such as age-related macular degeneration.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent11658030
dc.identifier.doi10.1186/s12964-025-02587-0
dc.identifier.issn1478-811X
dc.identifier.otherPURE: 149193089
dc.identifier.otherPURE UUID: 1887a461-280c-4fe8-a696-0028d7f872c6
dc.identifier.otherScopus: 105026212548
dc.identifier.otherPubMed: 41430718
dc.identifier.otherWOS: 001651195400002
dc.identifier.urihttp://hdl.handle.net/10362/199085
dc.identifier.urlhttps://www.scopus.com/pages/publications/105026212548
dc.language.isoeng
dc.peerreviewedyes
dc.subjectAge-related macular degeneration
dc.subjectExtracellular vesicles
dc.subjectMetalloproteinases
dc.subjectNeurodegeneration
dc.subjectNeuroinflammation
dc.subjectOuter blood-retinal barrier
dc.subjectRetinal pigment epithelial cells
dc.subjectBiochemistry
dc.subjectMolecular Biology
dc.subjectCell Biology
dc.titleRetinal pigment epithelium-derived extracellular vesicles mediate outer blood retinal barrier disruption in response to AMD-related stressen
dc.typejournal article
degois.publication.issue1
degois.publication.titleCell Communication and Signaling
degois.publication.volume23
dspace.entity.typePublication
rcaap.rightsopenAccess

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