Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells

Guillermo Lehmann; Michael Ginsberg; Daniel Nolan; Cristina Rodríguez; José Martínez-González; Shemin Zeng; Andrew Voigt; Robert Mullins; Shahin Rafii; Enrique Rodriguez-Boulan; Ignacio Benedicto

doi:10.3390/cells11192975

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Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells

Journal article

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Peer reviewed

Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells

Guillermo Lehmann, Michael Ginsberg, Daniel Nolan, Cristina Rodríguez, José Martínez-González, Shemin Zeng, Andrew Voigt, Robert Mullins, Shahin Rafii, Enrique Rodriguez-Boulan, …

Cells (Basel, Switzerland), Vol.11(19), p.2975

01/01/2022

DOI: 10.3390/cells11192975

PMCID: PMC9564307

PMID: 36230937

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Abstract

Alpha-2-macroglobulin (A2M) is a protease inhibitor that regulates extracellular matrix (ECM) stability and turnover. Here, we show that A2M is expressed by endothelial cells (ECs) from human eye choroid. We demonstrate that retinal pigment epithelium (RPE)-conditioned medium induces A2M expression specifically in ECs. Experiments using chemical inhibitors, blocking antibodies, and recombinant proteins revealed a key role of VEGF-A in RPE-mediated A2M induction in ECs. Furthermore, incubation of ECs with RPE-conditioned medium reduces matrix metalloproteinase-2 gelatinase activity of culture supernatants, which is partially restored after A2M knockdown in ECs. We propose that dysfunctional RPE or choroidal blood vessels, as observed in retinal diseases such as age-related macular degeneration, may disrupt the crosstalk mechanism we describe here leading to alterations in the homeostasis of choroidal ECM, Bruch’s membrane and visual function.

Cell Culture

Extracellular Matrix

Gene Expression

Pathogenesis

Visual Perception

a2-Macroglobulin

Age

Binding sites

Blocking antibodies

Blood vessels

Endothelial cells

Epithelium

Gelatinase

Homeostasis

Macular degeneration

Matrix metalloproteinase

Metalloproteinase

Photoreceptors

Proteinase inhibitors

Retina

Retinal pigment epithelium

Vascular endothelial growth factor

Details

Title: Subtitle: Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells
Creators: Guillermo Lehmann
Michael Ginsberg
Daniel Nolan
Cristina Rodríguez
José Martínez-González
Shemin Zeng
Andrew Voigt
Robert Mullins
Shahin Rafii
Enrique Rodriguez-Boulan
Ignacio Benedicto
Resource Type: Journal article
Publication Details: Cells (Basel, Switzerland), Vol.11(19), p.2975
DOI: 10.3390/cells11192975
PMID: 36230937
PMCID: PMC9564307
NLM abbreviation: Cells
eISSN: 2073-4409
Publisher: MDPI AG
Grant note: DOI: 10.13039/501100006541, name: Comunidad de Madrid, award: 2017-T1/BMD-5247, 2021-5A/BMD-20944; DOI: 10.13039/100000002, name: National Institutes of Health, award: EY08538, GM34107, EY024605; DOI: 10.13039/100009784, name: Starr Foundation, award: 2013-028; name: Ministerio de Ciencia e Innovación, Spain, award: CEX2020-001041-S, RTI2018-094727-B-100
Language: English
Date published: 01/01/2022
Academic Unit: The University of Iowa Institute for Vision Research; Internal Medicine; Ophthalmology and Visual Sciences
Record Identifier: 9984306259502771

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