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.

年龄相关性黄斑变性（AMD）是失明的主要原因。激光诱导的非人类灵长类动物脉络膜新生血管形成（CNV）是广泛使用的新生血管AMD动物模型。视网膜下纤维化（SFb）是有效的抗VEGF治疗新生血管AMD的主要限制因素，但尚未在灵长类CNV模型中对SFb进行过系统的分析，尚不清楚VEGF是否直接影响SFb。我们招募了大批恒河猴来研究SFb的发生，多模式成像和视网膜电图（ERG）特征以及相关的细胞因子。在这里，我们显示在33只猕猴中，有88％的CNV眼睛发育了SFb。光谱域光学相干断层扫描（SD-OCT）识别了灵长类动物中SFb的四种视网膜下超反射材料（SHRM）。多峰成像对于监测SFb是可靠的，并且与组织学结果非常匹配。振荡电位的降低幅度与视网膜内层的变薄相关，并且可能是SFb指标。Iba1⁺在纤维化病变中浸润的小胶质细胞/巨噬细胞，水细胞因子分析确定了四种与纤维化相关的因子（GM-CSF，IL-10，TGFβ2和VEGF）。出乎意料的是，我们发现VEGF的持续表达可能是SFb的重要诱导剂，而抗VEGF治疗实际上部分抑制了SFb。综上所述，我们的数据表明，激光诱导的灵长类动物SFb模型，加上多模态成像和ERG记录，是剖析SFb的发病机理并探讨其治疗原理的有用系统。对于AMD治疗，必须将抗VEGF和抗纤维化剂联合治疗。