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

Jie‐Hong Wu,Quan‐Wei He,Hai‐Ling Wang,Ling Mao,Yi‐Fan Zhou,Can‐Dong Hong,Yong Wang,Peng‐Cheng Li,Hui‐Juan Jin,Ya‐Nan Li,Yuan‐Peng Xia,Zhen‐Yu Yue,Bo Hu,An‐Qi Chen,Chun‐Lin Zhang

doi:10.15252/emmm.201810154

Abstract

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.

Highlights

Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness in working-aged people (Cheung et al, 2010)
To identify specific semaphorins that may contribute to the development of DR, we first performed a screening of the expression of semaphorins in two different models for DR: an STZ-induced mouse DR model, which develops only retinal vascular leakage without neovascularization (Olivares et al, 2017), and oxygen-induced retinopathy (OIR), an animal model of retinopathy of prematurity (ROP) with neovascularization and vascular leakage (Connor et al, 2009)
Our current study reports that an aberrant increase of Sema4D/PlexinB1 signaling leads to migration and permeability in endothelial cells and promotes the N-cadherin internalization and pericyte loss that worsen the vascular permeability in DR animal models (Fig 9)

Summary

Introduction

Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness in working-aged people (Cheung et al, 2010). For many of the patients with DME who respond to anti-VEGF therapy, the response may only be temporary These patients require frequent injections to control edema (Do et al, 2013; Channa et al, 2014; Ashraf et al, 2016). Some patients are resistant to anti-VEGF therapy, presenting a challenge with regard to effective disease management (Channa et al, 2014; Ashraf et al, 2016) These patients may experience persistent macular edema over time despite frequent anti-VEGF injections alone (Channa et al, 2014; Ashraf et al, 2016). There is a high demand for additional or alternative treatments to help those non- or poor responders to anti-VEGF and potentially reduce the number of injections

Methods

Results

Conclusion