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Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy

Diabetic retinopathy (DR) is a common complication of diabetes and leads to blindness. Anti‐VEGF is a primary treatment for DR. Its therapeutic effect is limited in non‐ or poor responders despite frequent injections. By performing a comprehensive analysis of the semaphorins family, we identified th...

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Autores principales: Wu, Jie‐hong, Li, Ya‐nan, Chen, An‐qi, Hong, Can‐dong, Zhang, Chun‐lin, Wang, Hai‐ling, Zhou, Yi‐fan, Li, Peng‐Cheng, Wang, Yong, Mao, Ling, Xia, Yuan‐peng, He, Quan‐wei, Jin, Hui‐juan, Yue, Zhen‐yu, Hu, Bo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005627/
https://www.ncbi.nlm.nih.gov/pubmed/31943789
http://dx.doi.org/10.15252/emmm.201810154
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author Wu, Jie‐hong
Li, Ya‐nan
Chen, An‐qi
Hong, Can‐dong
Zhang, Chun‐lin
Wang, Hai‐ling
Zhou, Yi‐fan
Li, Peng‐Cheng
Wang, Yong
Mao, Ling
Xia, Yuan‐peng
He, Quan‐wei
Jin, Hui‐juan
Yue, Zhen‐yu
Hu, Bo
author_facet Wu, Jie‐hong
Li, Ya‐nan
Chen, An‐qi
Hong, Can‐dong
Zhang, Chun‐lin
Wang, Hai‐ling
Zhou, Yi‐fan
Li, Peng‐Cheng
Wang, Yong
Mao, Ling
Xia, Yuan‐peng
He, Quan‐wei
Jin, Hui‐juan
Yue, Zhen‐yu
Hu, Bo
author_sort Wu, Jie‐hong
collection PubMed
description Diabetic retinopathy (DR) is a common complication of diabetes and leads to blindness. Anti‐VEGF is a primary treatment for DR. Its therapeutic effect is limited in non‐ or poor responders despite frequent injections. By performing a comprehensive analysis of the semaphorins family, we identified the increased expression of Sema4D during oxygen‐induced retinopathy (OIR) and streptozotocin (STZ)‐induced retinopathy. The levels of soluble Sema4D (sSema4D) were significantly increased in the aqueous fluid of DR patients and correlated negatively with the success of anti‐VEGF therapy during clinical follow‐up. We found that Sema4D/PlexinB1 induced endothelial cell dysfunction via mDIA1, which was mediated through Src‐dependent VE‐cadherin dysfunction. Furthermore, genetic disruption of Sema4D/PlexinB1 or intravitreal injection of anti‐Sema4D antibody reduced pericyte loss and vascular leakage in STZ model as well as alleviated neovascularization in OIR model. Moreover, anti‐Sema4D had a therapeutic advantage over anti‐VEGF on pericyte dysfunction. Anti‐Sema4D and anti‐VEGF also conferred a synergistic therapeutic effect in two DR models. Thus, this study indicates an alternative therapeutic strategy with anti‐Sema4D to complement or improve the current treatment of DR.
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spelling pubmed-70056272020-02-13 Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy Wu, Jie‐hong Li, Ya‐nan Chen, An‐qi Hong, Can‐dong Zhang, Chun‐lin Wang, Hai‐ling Zhou, Yi‐fan Li, Peng‐Cheng Wang, Yong Mao, Ling Xia, Yuan‐peng He, Quan‐wei Jin, Hui‐juan Yue, Zhen‐yu Hu, Bo EMBO Mol Med Articles Diabetic retinopathy (DR) is a common complication of diabetes and leads to blindness. Anti‐VEGF is a primary treatment for DR. Its therapeutic effect is limited in non‐ or poor responders despite frequent injections. By performing a comprehensive analysis of the semaphorins family, we identified the increased expression of Sema4D during oxygen‐induced retinopathy (OIR) and streptozotocin (STZ)‐induced retinopathy. The levels of soluble Sema4D (sSema4D) were significantly increased in the aqueous fluid of DR patients and correlated negatively with the success of anti‐VEGF therapy during clinical follow‐up. We found that Sema4D/PlexinB1 induced endothelial cell dysfunction via mDIA1, which was mediated through Src‐dependent VE‐cadherin dysfunction. Furthermore, genetic disruption of Sema4D/PlexinB1 or intravitreal injection of anti‐Sema4D antibody reduced pericyte loss and vascular leakage in STZ model as well as alleviated neovascularization in OIR model. Moreover, anti‐Sema4D had a therapeutic advantage over anti‐VEGF on pericyte dysfunction. Anti‐Sema4D and anti‐VEGF also conferred a synergistic therapeutic effect in two DR models. Thus, this study indicates an alternative therapeutic strategy with anti‐Sema4D to complement or improve the current treatment of DR. John Wiley and Sons Inc. 2020-01-13 2020-02-07 /pmc/articles/PMC7005627/ /pubmed/31943789 http://dx.doi.org/10.15252/emmm.201810154 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Wu, Jie‐hong
Li, Ya‐nan
Chen, An‐qi
Hong, Can‐dong
Zhang, Chun‐lin
Wang, Hai‐ling
Zhou, Yi‐fan
Li, Peng‐Cheng
Wang, Yong
Mao, Ling
Xia, Yuan‐peng
He, Quan‐wei
Jin, Hui‐juan
Yue, Zhen‐yu
Hu, Bo
Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy
title Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy
title_full Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy
title_fullStr Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy
title_full_unstemmed Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy
title_short Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy
title_sort inhibition of sema4d/plexinb1 signaling alleviates vascular dysfunction in diabetic retinopathy
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005627/
https://www.ncbi.nlm.nih.gov/pubmed/31943789
http://dx.doi.org/10.15252/emmm.201810154
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