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S.H. Lee, Y.S. You, H.J. Lim, S.J. Lee, O.W. Kwon, S.C. Lee; Dose–Dependent Biphasic Activity of EGT001 in Ocular Angiogenesis Model . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1912.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Retinopathy of prematurity (ROP) is a developmental vascular disease occurring in the incompletely vascularized retina of the premature infant. EGT001 is a polypeptide drug developing as an anti–angiogenic drug. However, it does not have anti–angiogenic effect, but pro–angiogenic effect in administration of low dosage. This study was aimed to reveal what EGT001 affect ocular angiogenesis according to dosage and to investigate its accurate biochemical mechanism on angiogenesis in eye. Methods:The effects of EGT001 were examined in oxygen–induced retinopathy (OIR) and VEGF–induced cornea micropocket in the mouse. In addition, the effect on maturation of vessel in treated with low dosage of EGT001 was investigated by means of the migratory response of BCE cells and the measurement of ability of human umbilical vein endothelial cell HUVEC cells to form three dimensional structures (tube formation). Western blotting of FAK and angiopoietin–1 (Ang–1) was also used to investigate the mechanism of cell migration and maturation concerned with neovascularization. Results: The mouse treated with low dosage of EGT001 (range form 1 µg/kg to 100 µg/kg) had significantly less oxygen–induced retinal neovascularization and formed near normal retinal vessel network. In the cornea micropocket assay, after daily intraperitoneal injection of 5 mg/kg of EGT001, neovascularization was inhibited in the cornea. However, the administration of low dosage (10 ng/kg and 1 µg/kg) of EGT001 promoted significantly neovascularity compared with VEGF only group. Fluorescent microscopic findings demonstrated enhanced length of vessel and vascular network maturation. Treatment with 10 nM of saxatilin appeared to induce significantly cell migration and promoted tube formation. In addition, EGT001 appeared to induce FAK overexpression and phosphorylation, which might be to the increase of cell migration. Interestingly, amount of Ang–1 increased in cell culture medium treated with more than 1µM of EGT001. Conclusions: These results indicate that EGT001 have both anti–angiogenic and pro–angiogenic effects in dose–dependent manner. This study showed that pro–angiogenic effect of EGT001 help oxygen damaged retinal vessel to mature vessel network without fibrosis. Therefore, EGT001 may be used as a drug for need of vessel normal maturation and stabilization on therapy of eye related diseases as ROP and diabetic retinopathy (DMR).
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