Multimodal imaging and electroretinography highlights the role of VEGF in the laser-induced subretinal fibrosis of monkey. (February 2021)

• Record Type: Journal Article
• Authors: Wang, Yujiao; Fang, Qiyao; Zhang, Chaomao; Chen, Yongjiang; Gou, Tao; Cai, Qinglin; Yin, Hongyu; Gao, Yunxia; Feng, Yuliang; Qiu, Shuang; Zhang, Ming; Cen, Xiaobo; Zhang, Hui; Chen, Danian
• Is Part Of: Experimental eye research. Volume 203(2021)
• Publication Date: 2021-02
• Subjects: Rhesus macaques -- Age-related macular degeneration -- Subretinal fibrosis -- Laser photocoagulation -- VEGF -- SHRM; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2020.108417
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Age-related macular degeneration (AMD) is a leading cause of blindness. Laser-induced nonhuman primate choroidal neovascularization (CNV) is a widely used animal model of neovascular AMD. Subretinal fibrosis (SFb) is the major limiting factor of effective anti-VEGF therapy for neovascular AMD, yet SFb has never been systematically analyzed in the primate CNV model and if VEGF directly affect SFb is unknown. We recruited a large cohort of rhesus macaques to study the occurrence, multimodal imaging and electroretinography (ERG) features, and related cytokines of SFb. Here we show that among 33 rhesus macaques, 88% CNV eyes developed SFb. Spectral domain optical coherence tomography (SD-OCT) identified four types of subretinal hyper-reflective material (SHRM) of SFb in primate. Multimodal imaging is reliable for monitoring SFb and matches the histological results well. Reduced amplitude of oscillatory potentials correlates with the thinning of inner retina layers and is a possible SFb indicator. Iba1 + microglia/macrophage cells infiltrated in the fibrotic lesions, and aqueous cytokine analysis identified four fibrosis-related factors (GM-CSF, IL-10, TGFβ2 and VEGF). Unexpectedly, we found sustained expression of VEGF may be an important inducer of SFb, and anti-VEGF therapy actually partially suppresses SFb. Taken together, our data suggest the laser-induced primate SFb model, coupled with multimodal imaging and ERG recording, is a useful system to dissect the pathogenesis and explore the rationale of treatment for SFb; and combined therapy with anti-VEGF and anti-fibrosis agents is necessary for AMD treatment. Highlights: Laser photocoagulation-induced primate choroidal neovascularization (CNV) can progress to subretinal fibrosis (SFb) in 1–2 years. About 88% CNV eyes develop SFb, however only 13% of them are vascular fibrosis. Based on the relationship between subretinal hyper-reflective material (SHRM) and retinal pigment epithelium (RPE), there are four types of fibrotic laser burns on spectral domain optical coherence tomography (SD-OCT). Full-field flash electroretinography (ERG) reveals abnormal oscillatory potentials in the primate model of SFb, which correlates with thinning of inner retinal layers. Sustained expression of VEGF may be an important inducer of SFb, and anti-VEGF therapy can partially suppress SFb.