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.

中文翻译：

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Sema4D / PlexinB1信号的抑制可减轻糖尿病性视网膜病变中的血管功能障碍。

糖尿病性视网膜病（DR）是糖尿病的常见并发症，并导致失明。抗VEGF是DR的主要治疗方法。尽管经常注射，但对非反应性或不良反应者的治疗效果有限。通过对信号蛋白家族进行全面分析，我们确定了Sema4D在氧诱导的视网膜病变（OIR）和链脲佐菌素（STZ）诱导的视网膜病变期间表达增加。在DR患者的水性液体中，可溶性Sema4D（sSema4D）的水平显着升高，并且在临床随访期间与抗VEGF治疗的成功呈负相关。我们发现Sema4D / PlexinB1通过mDIA1诱导内皮细胞功能障碍，这是通过Src依赖性VE-钙粘蛋白功能障碍介导的。此外，Sema4D / PlexinB1的遗传破坏或玻璃体内注射抗Sema4D抗体可减少STZ模型中的周细胞丢失和血管渗漏，并减轻OIR模型中的新血管形成。此外，抗Sema4D在抗周细胞功能障碍方面比抗VEGF具有治疗优势。抗Sema4D和抗VEGF在两个DR模型中也具有协同治疗作用。因此，该研究表明了用抗Sema4D替代治疗策略以补充或改善目前的DR治疗。