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，为眼内血管增生性疾病的治疗提供新的思路。在糖尿病视网膜病变中，周细胞丢失被认为会导致微血管不稳和血管高通透性。在链脲佐菌素诱导的糖尿病大鼠中，血管生成素2在糖尿病发病6个月后高表达，通过原位杂交和双重免疫染色分析，在表达血管生成素2的视网膜节段观察到周细胞丢失。(IOVS 2003；44；393-402)。在糖尿病视网膜病变中，血管紧张素-2选择性增强视网膜内皮细胞中的血管生成素-2，提示血管紧张素-2在内皮细胞和周细胞之间的关系中起作用。(《糖尿病》2001；50；867-875)。这些结果被高度评价为临床试验的基础数据，如直接研究。下一步，我们的目标是针对周细胞退化的血管进行新的治疗。将抗PDGFR-β的拮抗性单抗注射到新生小鼠体内，可导致视网膜血管周细胞丢失，这些小鼠的血管重塑较差，且存在渗漏。这个模型类似于糖尿病视网膜病变的病理变化。我们发现，添加重组修饰的血管生成素1恢复了一种分级的血管结构，也挽救了周细胞完全丧失的视网膜水肿和出血。这些观察证明了血管生成素1作为治疗糖尿病视网膜病变等疾病中周细胞丢失的一种新的治疗方法的潜力。(JCI 2002；110；1619-28)。血管生成素-1和血管紧张素-1受体阻滞剂有可能成为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.