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J. Ma, S.X. Zhang, J. Sima, C.K. Shao, C.E. Crosson, R.A. Saunders, M.E. Wilson; Treatment of Retinal Edema Using Peptide Angiogenic Inhibitors . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4029.
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Purpose: Retinal vascular leakage, as found in diabetic retinopathy and other ocular diseases, can lead to retinal edema and consequent vision loss. The purpose of this study was to determine the potential effect of peptide angiogenic inhibitors on vascular leakage. Methods: Oxygen-induced retinopathy (OIR) was induced by exposing neonatal Brown Norway rats to 75% oxygen for 5 days (P7 to P12). Experimental diabetes was induced in adult rats by streptozotocin (STZ, 60 mg/kg, i.v.). Rats received a single-dose intravitreal injection of an angiogenic inhibitor, plasminogen kringle 5 (K5), pigment epithelium-derived factor (PEDF) or kallikrein-binding protein (KBP) in the right eye and the same volume of phosphate-buffered saline (PBS) in the left eye as controls. Vascular leakage in the retina, iris and choroid was measured by Evans blue-albumin leakage method. VEGF levels were determined by Western blot analysis and immunohistochemistry. Results: Both OIR and STZ-diabetic rats showed abnormally high vascular permeability in the retina, iris and choroid compared to the age-matched normal rats. K5 significantly reduced the vascular permeability in both the OIR and STZ-diabetic animal models (P<0.01, n=4). However, no effect on permeability in normal rats was observed. Similarly, PEDF and KBP also showed dose-dependent inhibition of vascular leakage in these two animal models (P<0.05, n=4). The inhibition of vascular leakage occurred as early as 1 day after the injection and required 5-10-fold lower doses of the angiogenic inhibitors than those required for their anti-angiogenic activities. The reductions in vascular permeability after the K5 and PEDF injection correlated with the decreases of VEGF levels in the retina. Moreover, K5 inhibited the IGF-1-induced hyper-permeability which is known to be through up-regulation of endogenous VEGF expression, but had no effect on the hyper-permeability induced by injection of exogenous VEGF. KBP displayed a dose-dependent competition with VEGF in binding to the VEGF receptors in primary endothelial cells. Conclusions: Angiogenic inhibitors reduce pathological vascular leakage in the retina and thus, may reduce consequent retinal edema. This effect may be mediated, at least in part, by the down-regulation of endogenous VEGF expression or by interfering with VEGF binding to its receptors.
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