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K. Park, J.-X. Ma; Over-Expression of Pigment Epithelium-Derived Factor (PEDF) Inhibits Ischemia-Induced Retinal Inflammation and Neovascularization. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5694.
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PEDF is a secreted protein which is known as an inhibitor of angiogenesis and inflammation. The purpose of this study is to investigate the impact of genetic over-expression of PEDF on retinal vasculature in normal and ischemic conditions.
The PEDF transgenic construct was generated with the full-length human PEDF cDNA under the control of the chicken β-actin promoter to achieve over-expression of hPEDF in all tissues. Expression levels of PEDF were determined in serum and other tissues by Western blot analysis. The effect of PEDF over-expression on retinal development and function under normal conditions was determined by retinal histology analysis and ERG recording at 8 weeks of age. For the oxygen-induced retinopathy (OIR) model, the transgenic mice were exposed to 75% oxygen from postnatal days 7 to 12 to induce retinal neovascularization (NV). VEGF and ICAM-1 levels were measured by Western blot assay at P16 of age. The anti-angiogenic effect of over-expressing hPEDF was determined in OIR transgenic mice using pre-retinal vascular cell numbers and fluorescein retinal angiography at P18 of age.
High levels of PEDF were detected in the serum of transgenic mice. In the retina, PEDF levels were approximately 5.5-fold higher than that in the age-matched wild-type (wt) mice. Under normal conditions, the PEDF transgenic mice did not show any abnormalities in retinal histology and function at 8 weeks of age, suggesting that over-expression of PEDF did not affect the development of the retina. In the OIR model, however, the transgenic mice showed a less severe retinal NV and reduced pre-retinal neovascular cells, compared to the OIR mice in a wt background. Western blot analysis showed that retinal levels of inflammatory factors, VEGF and ICAM-1 were 2-fold lower in the OIR PEDF transgenic mice, compared to that in the OIR wt mice. As shown by albumin leakage in the retina, the PEDF transgenic mice had reduced retinal vascular leakage than wt mice with OIR.
Our studies demonstrated that over-expression of PEDF in the retina inhibits ischemia-induced retinal inflammation and NV. The PEDF transgenic mouse provides a useful model for studying the roles of the PEDF in neovascular disorders such as diabetic retinopathy.
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