VEGF-Angiopoietin-Tie2 System in Diabetic Retinopathy

Kim, Nan Hee; Kim, Hee Young; Seo, Ji A; Lee, Kye Won; Kim, Sin Gon; Choi, Kyung Mook; Baik, Sei Hyun; Park, Yoon Shin; Jo, Inho; Choi, Dong Seop

Abstract

BACKGROUND: Ischemia-induced neovascularization can cause the loss of vision in retinal disorders such as diabetic retinopathy. Recent studies have shown that the angiopoietin-Tie2 system is a major regulator of vascular integrity and it is involved in pathologic angiogenesis. However, its role in the pathophysiology of diabetic retinopathy is not yet known. We examined the regulation of the VEGF-angiopoietin-Tie2 system in both in vitro and in vivo studies to discover their possible role in diabetic retinopathy.
METHODS
We investigated the effects of a well-known angiogenic stimulus, hypoxia(2% O2 concentration) and vascular endothelial growth factor(VEGF, 10 ng/mL) on the expression of the angiopoietin-Tie2 mRNA in bovine retinal pericytes(BRP) and bovine aortic endothelial cells(BAEC). We also examined the expressions of VEGF-angiopoietin-Tie2 mRNA in retinas of type 2 diabetic OLETF(Otsuka-Long-Evans-Tokushima-Fatty) rats at 30 and 50 weeks. We also investigated the effect of angiotensin II receptor type 1(AT1) antagonist on the VEGFangiopoietin-Tie2 expression.
RESULTS
Hypoxia and VEGF treatment significantly increased angiopoietin-1(Ang1) mRNA expression in the BRPs. In contrast, the angiopoietin-2(Ang2) mRNA expression was unaltered in the BRPs treated with hypoxia and VEGF. Significant up-regulation of Tie2 mRNA expression was found and this lasted up to 12 h. However, using BAECs, we found that only the Ang2 expression responded to these two angiogenic stimuli. In OLETF rats, the Ang-Tie2 expression patterns were similar with those of the BAECs. Ang2 and VEGF mRNA were increased at 30 and 50 weeks for the OLETF rats, whereas the Ang1 expression was not changed. The up-regulation of Ang2 and VEGF was decreased with the losartan treatment, an AT1 receptor antagonist. Tie2 mRNA expression was increased only at 50 weeks and it did not show any decrement by the losartan treatment.
CONCLUSION
Our data suggest that hypoxia and VEGF treatment differentially regulate the angiopoietin-Tie2 system in the two vascular cells. Ang2 and VEGF expressions were predominantly increased in type 2 diabetic rats, and the unopposed action of Ang2 with VEGF might be involved in the development of diabetic retinopathy. The renin-angiotensin system may be a potential mechanism for the up-regulated VEGF-Ang2 system