|Budget Amount *help
¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 2002: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥4,500,000 (Direct Cost: ¥4,500,000)
Diabetic retinopathy has been recognized as a major cause of blindness especially in the working age population. Although VEGF has been reported to involved in the initiation and progression of diabetic retinopathy, the precise mechanisms including its receptors and cell signaling remained largely unclear. The aim of the study of this period was to elucidate the precise mechanisms of VEGF intiating and progressing diabetic retinopathy. It was widely accepted that diabetic retinopathy has three fundamental vascular disorders: vascular hyperpermeability, micro-vascular occlusion, and angiogenesis. We initially examined the causal relationships between VEGF-KDR system and the vascular hyperpermeability using the in vitro double chamber system. We confirmed that VEGF-E, a VEGFR-2 (KDR) specific ligand, could increase the vascular permeability, while PlGF, a VEGFR-1 (flt-1) specific ligand, could not. We thus suggested that VEGF regulated the vascular hyperpermeability mainly through KDR. W
e also confirmed that VEGF could increase the expression of TF, the initiator of external coagulation cascade, in retinal capillary endothelial cells both in vivo and in vitro. In addition, we demonstrated that VEGF-induced TF expression was mediated through p44/p42 MAP kinase and the transcription factor Egr-1. These findings supported the possibility that VEGF-KDR system could promote micro-vascular occlusion. Since VEGF-KDR system has been recognized to regulate ocular angiogenesis, VEGF-KDR system plays a pivotal role to initiate and progress three fundamental vascular disorders in diabetic retinas. From these findings, we hypothesize the suppression of the VEGF-KDR system is the key strategy to inhibit the blindness due to diabetic retinopathy. We next revealed that PPARγ ligands could suppress the KDR gene expression through the suppression of interaction between Sp1/Sp3 and its promoter region. We also demonstrated that PPARγ ligands could suppress rodent angiogenesis models in vivo. These findings showed that PPARγ ligands are hopeful drugs to treat diabetic retinopathy through the inhibition of VEGF and its receptor system as well as SU5416 which is one of KDR-selective tyrosine kinase inhibitors.
We also examined the expression of pigment epithelium-derived growth factor (PEDF), known as one of the angiogenesis inhibitors, using cultured retinal cells and hyalocytes. PEDF was broadly expressed by cultured cells such as glial cells, pericytes and hyalocytes in addition to retinal pigment epithelial cells. These results suggested that many cell types are involved in the regulation of intraocular angiogenesis. In addition, hyalocytes might play an important role to keep the vitreous cavity as avascular area through the function of PEDF. Less