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J-X Ma, G Gao, Y Li, S Gee, J Fant, CE Crosson, A Dudley; Angiogenic Inhibitor K5 Inhibits Retinal Neovascularization Possibly through Down-regulation of VEGF and Up-regulation of PEDF . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1279.
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Purpose:We have previously shown that intravitreal injection of plasminogen kringle 5 (K5), a potent angiogenic inhibitor, inhibits ischemia-induced retinal neovascularization in a rat model. This study was designed to determine the effect of K5 on the regulation of angiogenic homeostasis. Methods:Primary human retinal capillary endothelial cells (HRCEC) and pericytes were isolated, cultured and characterized from donor eyes. Retinal neovascularization was induced in Brown Norway rats by exposure to hyperoxia followed by normoxia. Changes in vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) were determined by Western and Northern blot analyses. HIF-1α nuclear translocation was evaluated by measuring the nuclear levels of HIF-1α. MAP kinase activation was determined by comparison of its phosphorylation level to total MAP kinase. Results:K5 down-regulated an endogenous angiogenic stimulator, VEGF, and up-regulated an angiogenic inhibitor, PEDF, in a dose-dependent manner in primary vascular cells and in rat retinas. Changes in VEGF and PEDF expression by K5 in the retina were correlated with its anti-angiogenic activity in a rat model of ischemia-induced retinopathy. Retinal RNA levels of VEGF and PEDF were also changed by K5. K5 inhibited bFGF-induced p42/p44 MAP kinase activation and ischemia-induced nuclear translocation of HIF-1α. Conclusion:Down-regulation of endogenous angiogenic stimulators and up-regulation of endogenous angiogenic inhibitors, thus leading toward restoration of the balance in angiogenic control, may represent a mechanism for the anti-angiogenic activity of K5. The decreased activation of HIF-1 and p42/p44 MAP kinase may be responsible for the down-regulation of VEGF expression by K5.
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