Li Tao, Aredo Bogale, Zhang Kaiyan, Zhong Xin, Pulido Jose S, Wang Shusheng, He Yu-Guang, Huang Xianming, Brekken Rolf A, Ufret-Vincenty Rafael L
Department of Ophthalmology University of Texas Southwestern Medical Center, Dallas, Texas, United States 2Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of Chi.
Department of Ophthalmology University of Texas Southwestern Medical Center, Dallas, Texas, United States.
Invest Ophthalmol Vis Sci. 2015 Nov;56(12):7137-45. doi: 10.1167/iovs.15-17302.
Choroidal neovascularization (CNV) accounts for 90% of cases of severe vision loss in patients with advanced age-related macular degeneration. Identifying new therapeutic targets for CNV may lead to novel combination therapies to improve outcomes and reduce treatment burden. Our goal was to test whether phosphatidylserine (PS) becomes exposed in the outer membrane of choroidal neovascular endothelium, and whether this could provide a new therapeutic target for CNV.
Choroidal neovascularization was induced in C57BL/6J mice using laser photocoagulation. Choroidal neovascularization lesions costained for exposed PS and for intercellular adhesion molecule 2 (or isolectin B4) were imaged in flat mounts and in cross sections. The laser CNV model and a choroidal sprouting assay were used to test the effect of PS-targeting antibodies on choroidal angiogenesis. Choroidal neovascularization lesion size was determined by intercellular adhesion molecule 2 (ICAM-2) staining of flat mounts.
We found that PS was exposed in CNV lesions and colocalized with vascular endothelial staining. Treatment with PS-targeting antibodies led to a 40% to 80% reduction in CNV lesion area when compared to treatment with a control antibody. The effect was the same as that seen using an equal dose of an anti-VEGF antibody. Results were confirmed using the choroid sprouting assay, an ex vivo model of choroidal angiogenesis.
We demonstrated that PS is exposed in choroidal neovascular endothelium. Furthermore, targeting this exposed PS with antibodies may be of therapeutic value in CNV.
脉络膜新生血管（CNV）是导致晚期年龄相关性黄斑变性患者严重视力丧失的90%的病例原因。确定CNV的新治疗靶点可能会带来新的联合疗法，以改善治疗效果并减轻治疗负担。我们的目标是测试磷脂酰丝氨酸（PS）是否会在脉络膜新生血管内皮细胞膜外暴露，以及这是否能为CNV提供一个新的治疗靶点。
使用激光光凝法在C57BL/6J小鼠中诱导脉络膜新生血管形成。对脉络膜新生血管病变进行PS暴露和细胞间黏附分子2（或异凝集素B4）双重染色，在平铺标本和横截面中成像。使用激光CNV模型和脉络膜芽生试验来测试靶向PS的抗体对脉络膜血管生成的影响。通过平铺标本的细胞间黏附分子2（ICAM-2）染色来确定脉络膜新生血管病变大小。
我们发现PS在CNV病变中暴露，并与血管内皮染色共定位。与对照抗体治疗相比，靶向PS的抗体治疗使CNV病变面积减少了40%至80%。其效果与使用等量抗VEGF抗体时相同。使用脉络膜芽生试验（脉络膜血管生成的离体模型）证实了结果。
我们证明了PS在脉络膜新生血管内皮中暴露。此外，用抗体靶向这种暴露的PS可能对CNV具有治疗价值。
