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

Jie hong Wu, Ya nan Li, An qi Chen, Can dong Hong, Chun lin Zhang, Hai ling Wang, Yi fan Zhou, Peng Cheng Li, Yong Wang, Ling Mao, Yuan peng Xia, Quan wei He, Hui juan Jin, Zhen yu Yue, Bo Hu

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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.

Original languageEnglish
Article numbere10154
JournalEMBO Molecular Medicine
Volume12
Issue number2
DOIs
StatePublished - 7 Feb 2020

Keywords

  • N-cadherin
  • Sema4D
  • diabetic retinopathy
  • mDIA1

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