Abstract
Abstract: :
Purpose: Recently, not only VEGF but also angiotensin II (AII) has been reported to be associated with the pathophysiology of proliferative diabetic retinopathy (PDR). To investigate whether AII modulates VEGF–induced neovascularization, we examined the effect of olmesartan medoxomil (CS–866), an AII type 1 (AT1) receptor antagonist, on retinal neovascularization and VEGF upregulation in mouse oxygen–induced retinopathy (OIR), and on VEGF–induced rabbit corneal neovascularization. Methods: (Exp. 1) C57BL/6 mice were exposed to 70–75% oxygen from postnatal day 7 (P7) for 5 days and then recovered in a room air for 5 days. CS–866 (1, 3 and 10 mg/kg, p.o.) or SU–5416 (3 and 10 mg/kg, i.p.), an inhibitor of VEGF receptor–2 tyrosine kinase, was administered to the pups from P7 for 5 days. At P12, their eyes were enucleated and stained with ADPase. Retinal neovascularization was graded according to the method by Zhang et al. (Invest. Ophthalmol. Vis. Sci. 2000). Retinal VEGF protein was measured by ELISA in satellite animals treated with CS–866. (Exp. 2) Hydron pellets containing recombinant human VEGF were inserted into pockets formed surgically in the cornea of NZW rabbits. CS–866 (10 mg/kg, p.o.) was administered to rabbits for 7 days post operatively. The rabbit eyes were then photographed and corneal neovascularization was assessed according to the method by Ziehe et al. (J. Clin. Invest. 1994). Results: (Exp. 1) CS–866 and SU–5416 significantly prevented mouse retinal neovascularization. In mice with OIR, retinal VEGF protein content was increased by approximately fourfold compared to that in normal mice. CS–866 had weak or no effect on the level of VEGF content in mice with OIR. (Exp. 2) CS–866 at 10 mg/kg significantly prevented VEGF–induced corneal neovascularization in rabbits. Conclusions: The results support the idea that both AII and VEGF are involved in mouse OIR. AII may have a significant role in the VEGF–induced vascular formation rather than in the regulation of retinal VEGF content in the mouse model. A specific and potent AT1 receptor antagonist is considered to have therapeutic potential for treating ocular diseases associated with abnormal neovascularization, including PDR, in which VEGF has a predominant role.
Keywords: retina • retinal neovascularization • pharmacology