The pathological investigation of proliferative diabetic retinopathy based on the control of retinal pericytes

本研究旨在探讨视网膜内皮细胞和周细胞的调控机制，为眼内血管增殖性疾病的治疗开辟新的途径。在糖尿病视网膜病变中，周细胞的丢失可引起微动脉瘤和血管高渗透性。在链脲祖菌素诱导的糖尿病大鼠中，通过RT-PCR分析证实，血管生成素2在糖尿病发病6个月后高表达，通过原位杂交和双免疫染色分析，在血管生成素2表达的视网膜细胞中观察到周细胞丢失。(IOVS 2003; 44; 393年- 402年)。在糖尿病视网膜病变的眼睛中，血管紧张素2选择性地增强视网膜内皮细胞中的血管生成素2，这提示血管紧张素2在内皮细胞和周细胞之间的关系中的作用。(糖尿病2001;50,867 - 875年)。这些结果作为DIRECT研究等临床试验的基础数据得到了高度评价。在接下来，我们的目标是一个新的治疗发展，其中周细胞退化的血管。将一种针对pdgfr - β的拮抗单克隆抗体注射到新生小鼠体内，会导致视网膜血管的周细胞丢失，并且这些小鼠的血管会出现重构不良和渗漏。该模型类似于糖尿病视网膜病变的病理改变。我们发现，添加重组修饰的血管生成素1恢复了分层血管，并在完全没有周细胞的情况下挽救了视网膜水肿和出血。这些观察结果表明血管生成素1作为治疗糖尿病视网膜病变等疾病周细胞损失的一种新的治疗方式的潜力。(JCI 2002; 110; 1619 - 28)。血管生成素1和血管紧张素1型受体阻滞剂可能是治疗糖尿病视网膜病变的有效药物。

In this research, we investigated the control mechanism of retinal endothelial cells and pericytes, and aimed at a new therapeutic development of intraocular vascular proliferative diseases. In a diabetic retinopathy, pericyte loss is known to cause microaneuiysms and vascular hyperpermiability. In streptozotocine-induced diabetic rats, angiopoietine 2 is proved to be highly expressed after 6 months from onset of diabetes by RT-PCR analyses, and pericyte loss is observed by in situ hybridization and double immune staining analyses in the retinal cite where angiopoietine 2 is expressed. (IOVS 2003;44;393-402). In the eyes of diabetic retinopathy, angiotensin 2 selectively potentiates angiopoietine 2 in retinal endothelial cells, and this suggests the role of angiotensin 2 in the relation between endothelial cells and pericytes. (Diabetes 2001;50;867-875). These results are highly evaluated as a basic data on clinical trials, such as DIRECT study. In the next, we aimed a new therapeutic development on such vessels in which pericytes are degenerated. The injection of an antagonistic mAb against PDGFR-beta into murine neonates provides such pericyte loss of retinal vessels, and vessels of such mice are poorly remodeled and leaky. This model resembles a pathological change in diabetic retinopathy. We show that addition of recombinant modified angiopoietin 1 restored a hierarchical valculature, and also rescued retinal edema and hemorrhage in the complete absensce of pericytes. These observations demonstrate the potential of angiopoietin 1 as a new therapeutic modality for pericyte loss in diseases such as diabetic retinopathies. (JCI 2002;110;1619-28). Angiopoietin 1 and angiotensin type 1 receptor blocker are possible to be an effective drug in a diabetic retinopathy.