Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-09-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/19/2975 |
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| author | Guillermo L. Lehmann Michael Ginsberg Daniel J. Nolan Cristina Rodríguez José Martínez-González Shemin Zeng Andrew P. Voigt Robert F. Mullins Shahin Rafii Enrique Rodriguez-Boulan Ignacio Benedicto |
| author_facet | Guillermo L. Lehmann Michael Ginsberg Daniel J. Nolan Cristina Rodríguez José Martínez-González Shemin Zeng Andrew P. Voigt Robert F. Mullins Shahin Rafii Enrique Rodriguez-Boulan Ignacio Benedicto |
| author_sort | Guillermo L. Lehmann |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T21:55:15Z |
| format | Article |
| id | doaj.art-eda73ce701ce4b7fb8574dc854015da5 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T21:55:15Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-eda73ce701ce4b7fb8574dc854015da52023-11-23T20:00:27ZengMDPI AGCells2073-44092022-09-011119297510.3390/cells11192975Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial CellsGuillermo L. Lehmann0Michael Ginsberg1Daniel J. Nolan2Cristina Rodríguez3José Martínez-González4Shemin Zeng5Andrew P. Voigt6Robert F. Mullins7Shahin Rafii8Enrique Rodriguez-Boulan9Ignacio Benedicto10Margaret Dyson Vision Research Institute, Department of Ophthalmology, Weill Cornell Medicine, New York, NY 10065, USAAngiocrine Bioscience, Inc., San Diego, CA 92121, USAAngiocrine Bioscience, Inc., San Diego, CA 92121, USAInstitut de Recerca Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, SpainInstitut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), 08041 Barcelona, SpainInstitute for Vision Research, Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA 52246, USAInstitute for Vision Research, Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA 52246, USAInstitute for Vision Research, Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA 52246, USAAnsary Stem Cell Institute, Department of Medicine, Division of Regenerative Medicine, Weill Cornell Medicine, New York, NY 10065, USAMargaret Dyson Vision Research Institute, Department of Ophthalmology, Weill Cornell Medicine, New York, NY 10065, USAMargaret Dyson Vision Research Institute, Department of Ophthalmology, Weill Cornell Medicine, New York, NY 10065, USAAlpha-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.https://www.mdpi.com/2073-4409/11/19/2975Alpha-2-macroglobulin (A2M)retinal pigment epithelium (RPE)vascular endothelial growth factor-A (VEGF-A)endothelial cells (ECs)extracellular matrix (ECM)matrix metalloproteinase-2 (MMP-2) |
| spellingShingle | Guillermo L. Lehmann Michael Ginsberg Daniel J. Nolan Cristina Rodríguez José Martínez-González Shemin Zeng Andrew P. Voigt Robert F. Mullins Shahin Rafii Enrique Rodriguez-Boulan Ignacio Benedicto Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells Cells Alpha-2-macroglobulin (A2M) retinal pigment epithelium (RPE) vascular endothelial growth factor-A (VEGF-A) endothelial cells (ECs) extracellular matrix (ECM) matrix metalloproteinase-2 (MMP-2) |
| title | Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells |
| title_full | Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells |
| title_fullStr | Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells |
| title_full_unstemmed | Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells |
| title_short | Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells |
| title_sort | retinal pigment epithelium secreted vegf a induces alpha 2 macroglobulin expression in endothelial cells |
| topic | Alpha-2-macroglobulin (A2M) retinal pigment epithelium (RPE) vascular endothelial growth factor-A (VEGF-A) endothelial cells (ECs) extracellular matrix (ECM) matrix metalloproteinase-2 (MMP-2) |
| url | https://www.mdpi.com/2073-4409/11/19/2975 |
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