Kasai Atsushi
Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
Yakugaku Zasshi. 2011;131(8):1201-6. doi: 10.1248/yakushi.131.1201.
Progression of ischemic retinal diseases, such as diabetic retinopathy, is closely associated with pathological retinal angiogenesis mainly induced by vascular endothelial growth factor (VEGF). Anti-angiogenic therapy using anti-VEGF antibodies is effective in treating diabetic retinopathy, even though its efficacy is not long-lasting. Since many factors are involved in angiogenesis, it is reasonable to seek new therapeutic target molecules in pathological retinal angiogenesis. We have found that apelin/APJ system is involved in not only physiological but also pathological retinal angiogenesis using a mouse model of oxygen-induced retinopathy (OIR). Oxygen-induced vessel loss in the retinas of OIR model leads to a significant increase in the capillary density accompanied by abnormal vessel growth, similar to aneurysms, which are hardly detected in the retinas of control mice. Compared with age-matched control mice, retinal apelin expression was dramatically increased during retinal angiogenesis in OIR model. Immunostaining for APJ, apelin receptor, in retinal from OIR model revealed that APJ was localized in proliferating endothelial cells in the retinal vascular plexus. Retinal angiogenesis in the OIR model was rarely observed in apelin deficient mice, although temporal expression pattern of VEGF was similar to that of wild-type OIR model. In addition, clinical study showed that vitreous concentrations of apelin were significantly higher in the proliferative diabetic retinopathy group than in the control group. Taken together, these findings clearly suggest that apelin/APJ system may be a crucial factor for pathological retinal angiogenesis. Inhibition of this system could offer new therapeutic opportunities against ischemic retinopathy.
缺血性视网膜疾病（如糖尿病性视网膜病变）的进展与主要由血管内皮生长因子（VEGF）诱导的病理性视网膜血管生成密切相关。使用抗VEGF抗体的抗血管生成疗法在治疗糖尿病性视网膜病变方面是有效的，尽管其疗效并不持久。由于血管生成涉及许多因素，因此在病理性视网膜血管生成中寻找新的治疗靶点分子是合理的。我们利用氧诱导视网膜病变（OIR）小鼠模型发现，apelin/APJ系统不仅参与生理性视网膜血管生成，还参与病理性视网膜血管生成。OIR模型小鼠视网膜中的氧诱导血管丢失导致毛细血管密度显著增加，并伴有异常血管生长，类似于动脉瘤，而在对照小鼠的视网膜中几乎检测不到。与年龄匹配的对照小鼠相比，OIR模型中视网膜血管生成期间视网膜apelin表达显著增加。对OIR模型视网膜中的APJ（apelin受体）进行免疫染色显示，APJ定位于视网膜血管丛中增殖的内皮细胞。在apelin缺陷小鼠中很少观察到OIR模型中的视网膜血管生成，尽管VEGF的时间表达模式与野生型OIR模型相似。此外，临床研究表明，增殖性糖尿病视网膜病变组玻璃体液中apelin的浓度明显高于对照组。综上所述，这些发现清楚地表明，apelin/APJ系统可能是病理性视网膜血管生成的关键因素。抑制该系统可能为缺血性视网膜病变提供新的治疗机会。
