Extracellular vesicles from retinal pigment epithelium: Key players in the outer blood-retinal barrier disruption and choroidal neovascularization in age-related macular degeneration

IF 3 3区医学 Q1 OPHTHALMOLOGY

Acta Ophthalmologica Pub Date : 2025-01-19 DOI:10.1111/aos.16937

Beatriz Martins, Teresa Rodrigues, Raquel Boia, José Ramalho, António Francisco Ambrósio, Henrique Girão, Rosa Fernandes

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引用次数: 0

Abstract

Aims/Purpose: Age-related macular degeneration (AMD), a degenerative disease causing irreversible central vision loss in the elderly, is characterized by dysregulation of the retinal pigment epithelium (RPE). During AMD, stressed RPE releases extracellular vesicles (EVs) carrying bioactive cargo, potentially disrupting the outer blood-retinal barrier (oBRB) and accelerating AMD progression. Mechanisms behind EV-induced oBRB disruption and their role in choroidal neovascularization (CNV) are unclear. Our study aims to assess how RPE-derived EVs under inflammatory conditions impact oBRB integrity and CNV in AMD.

Methods: We used highly polarized primary cultures of porcine RPE (pRPE), porcine eyecups with the RPE exposed, and human umbilical vein endothelial cells (HUVEC). RPE and HUVEC cells were treated with TNF, LPS, or EVs derived from inflamed RPE cells. Additionally, Balb/c mice were intravitreally injected with RPE-derived EVs.

Results: Treatment with TNF or LPS reduced the transepithelial resistance (TER) of pRPE cells monolayer and disrupted the tight junction complexes. Although inflammatory stimuli reduced EVs release from the apical membrane of RPE cells, increased CD63 levels and MMPs levels and activity were found in EVs. Moreover, these EVs led to the disruption of the RPE monolayer. In the Matrigel assay of HUVEC, angiogenesis was induced by both TNF and LPS, and by RPE-derived EVs isolated after the LPS stimulus. At seven days following intravitreal injection, EVs induced outer retinal structural changes in the Balb/c mice.

Conclusions: Our study indicates that EVs released from RPE cells following an inflammatory insult contribute to the oBRB disruption and induce neovascularization, indicating that EVs may play a key role in the onset and progression of AMD.

Support: GOAP, Bayer; FCT, Portugal: 2020.04811.BD (to BM), PEst UIDB/04539/Base/2020 and UIDP/04539/Programatico/2020 through POCI-01-0145-FEDER-007440, CENTRO-01-0145-FEDER-000008: BRAINHEALTH2020

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来源期刊

Acta Ophthalmologica 医学-眼科学

CiteScore

7.60

自引率

5.90%

发文量

433

审稿时长

6 months

期刊介绍： Acta Ophthalmologica is published on behalf of the Acta Ophthalmologica Scandinavica Foundation and is the official scientific publication of the following societies: The Danish Ophthalmological Society, The Finnish Ophthalmological Society, The Icelandic Ophthalmological Society, The Norwegian Ophthalmological Society and The Swedish Ophthalmological Society, and also the European Association for Vision and Eye Research (EVER). Acta Ophthalmologica publishes clinical and experimental original articles, reviews, editorials, educational photo essays (Diagnosis and Therapy in Ophthalmology), case reports and case series, letters to the editor and doctoral theses.