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Role of Erythropoietin Receptor Signaling in Macrophages or Choroidal Endothelial Cells in Choroidal Neovascularization

Erythropoietin (EPO) has been proposed to reduce the progression of atrophic age-related macular degeneration (AMD) due to its potential role in neuroprotection. However, overactive EPO receptor (EPOR) signaling increased laser-induced choroidal neovascularization (CNV) and choroidal macrophage numb...

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Autores principales: Ramshekar, Aniket, Bretz, Colin A., Kunz, Eric, Cung, Thaonhi, Richards, Burt T., Stoddard, Gregory J., Hageman, Gregory S., Chaqour, Brahim, Hartnett, M. Elizabeth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9312702/
https://www.ncbi.nlm.nih.gov/pubmed/35884958
http://dx.doi.org/10.3390/biomedicines10071655
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author Ramshekar, Aniket
Bretz, Colin A.
Kunz, Eric
Cung, Thaonhi
Richards, Burt T.
Stoddard, Gregory J.
Hageman, Gregory S.
Chaqour, Brahim
Hartnett, M. Elizabeth
author_facet Ramshekar, Aniket
Bretz, Colin A.
Kunz, Eric
Cung, Thaonhi
Richards, Burt T.
Stoddard, Gregory J.
Hageman, Gregory S.
Chaqour, Brahim
Hartnett, M. Elizabeth
author_sort Ramshekar, Aniket
collection PubMed
description Erythropoietin (EPO) has been proposed to reduce the progression of atrophic age-related macular degeneration (AMD) due to its potential role in neuroprotection. However, overactive EPO receptor (EPOR) signaling increased laser-induced choroidal neovascularization (CNV) and choroidal macrophage number in non-lasered mice, which raised the question of whether EPOR signaling increased CNV through the recruitment of macrophages to the choroid that released pro-angiogenic factors or through direct angiogenic effects on endothelial cells. In this study, we addressed the hypothesis that EPOR signaling increased CNV by direct effects on macrophages or endothelial cells. We used tamoxifen-inducible macrophage-specific or endothelial cell-specific EPOR knockout mice in the laser-induced CNV model, and cultured choroidal endothelial cells isolated from adult human donors. We found that macrophage-specific knockout of EPOR influenced laser-induced CNV in females only, whereas endothelial-specific knockout of EPOR reduced laser-induced CNV in male mice only. In cultured human choroidal endothelial cells, knockdown of EPOR reduced EPO-induced signal transducer and activator of transcription 3 (STAT3) activation. Taken together, our findings suggest that EPOR signaling in macrophages or choroidal endothelial cells regulates the development of CNV in a sex-dependent manner. Further studies regarding the role of EPO-induced signaling are required to assess EPO safety and to select or develop appropriate therapeutic approaches.
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spelling pubmed-93127022022-07-26 Role of Erythropoietin Receptor Signaling in Macrophages or Choroidal Endothelial Cells in Choroidal Neovascularization Ramshekar, Aniket Bretz, Colin A. Kunz, Eric Cung, Thaonhi Richards, Burt T. Stoddard, Gregory J. Hageman, Gregory S. Chaqour, Brahim Hartnett, M. Elizabeth Biomedicines Article Erythropoietin (EPO) has been proposed to reduce the progression of atrophic age-related macular degeneration (AMD) due to its potential role in neuroprotection. However, overactive EPO receptor (EPOR) signaling increased laser-induced choroidal neovascularization (CNV) and choroidal macrophage number in non-lasered mice, which raised the question of whether EPOR signaling increased CNV through the recruitment of macrophages to the choroid that released pro-angiogenic factors or through direct angiogenic effects on endothelial cells. In this study, we addressed the hypothesis that EPOR signaling increased CNV by direct effects on macrophages or endothelial cells. We used tamoxifen-inducible macrophage-specific or endothelial cell-specific EPOR knockout mice in the laser-induced CNV model, and cultured choroidal endothelial cells isolated from adult human donors. We found that macrophage-specific knockout of EPOR influenced laser-induced CNV in females only, whereas endothelial-specific knockout of EPOR reduced laser-induced CNV in male mice only. In cultured human choroidal endothelial cells, knockdown of EPOR reduced EPO-induced signal transducer and activator of transcription 3 (STAT3) activation. Taken together, our findings suggest that EPOR signaling in macrophages or choroidal endothelial cells regulates the development of CNV in a sex-dependent manner. Further studies regarding the role of EPO-induced signaling are required to assess EPO safety and to select or develop appropriate therapeutic approaches. MDPI 2022-07-09 /pmc/articles/PMC9312702/ /pubmed/35884958 http://dx.doi.org/10.3390/biomedicines10071655 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ramshekar, Aniket
Bretz, Colin A.
Kunz, Eric
Cung, Thaonhi
Richards, Burt T.
Stoddard, Gregory J.
Hageman, Gregory S.
Chaqour, Brahim
Hartnett, M. Elizabeth
Role of Erythropoietin Receptor Signaling in Macrophages or Choroidal Endothelial Cells in Choroidal Neovascularization
title Role of Erythropoietin Receptor Signaling in Macrophages or Choroidal Endothelial Cells in Choroidal Neovascularization
title_full Role of Erythropoietin Receptor Signaling in Macrophages or Choroidal Endothelial Cells in Choroidal Neovascularization
title_fullStr Role of Erythropoietin Receptor Signaling in Macrophages or Choroidal Endothelial Cells in Choroidal Neovascularization
title_full_unstemmed Role of Erythropoietin Receptor Signaling in Macrophages or Choroidal Endothelial Cells in Choroidal Neovascularization
title_short Role of Erythropoietin Receptor Signaling in Macrophages or Choroidal Endothelial Cells in Choroidal Neovascularization
title_sort role of erythropoietin receptor signaling in macrophages or choroidal endothelial cells in choroidal neovascularization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9312702/
https://www.ncbi.nlm.nih.gov/pubmed/35884958
http://dx.doi.org/10.3390/biomedicines10071655
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