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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Published in:	EMBO molecular medicine 2020-02, Vol.12 (2), p.e10154-n/a
Main Authors:	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
Format:	Article
Language:	eng
Subjects:	Binding sites Blindness Cadherin Diabetes Diabetes mellitus Diabetic retinopathy Edema Endothelial cells Hypoxia Ischemia mDIA1 N‐cadherin Proteins Retina Retinopathy Rodents Sema4D Semaphorins Streptozocin Transcription factors Vascular endothelial growth factor Vascularization
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Summary:	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. Synopsis Retinal pericyte loss, vascular leakage and neovascularization are the main pathological changes during Diabetic Retinopathy (DR). Here we show that Sema4D/PlexinB1 signaling critically contributes to these processes, and is a therapeutic target in this context. Sema4D was increased in aqueous fluid of DR patients and in retinas of several mouse DR models. Sema4D/PlexinB1 signaling induced both endothelial cell and pericyte dysfunction. Inhibition of Sema4D/PlexinB1 alleviated vascular dysfunction in DR models. Anti‐Sema4D and anti‐VEGF exhibited a synergistic therapeutic effect. Retinal pericyte loss, vascular leakage and neovascularization are the main pathological changes during Diabetic Retinopathy (DR). Here we show that Sema4D/PlexinB1 signaling critically contributes to these processes, and is a therapeutic target in this context.
ISSN:	1757-4676 1757-4684