Angiostatin Decreases Vascular Leakage by Down-regulating VEGF Expression

Abstract

Abstract: : Purpose: Vascular leakage in the retina is known to cause macular edema and consequently, vision loss. The present study was designed to determine whether angiostatin, an angiogenic inhibitor, could inhibit vascular leakage in the retina, choroid and iris. Methods: The effect of angiostatin on vascular leakage was evaluated using a rat model of oxygen-induced retinopathy (OIR) and in rats with streptozotocin-induced (STZ) diabetes. The right eye received a single-dose intravitreal injection of angiostatin and the left eye received the same volume of phosphate-buffered saline (PBS) as control. Using the Evans blue method, we measured the vascular permeability changes in the retina, choroid and iris 1, 2 and 3 days after the injection. Fluorescein retinal angiography was performed on day 7 after the injection. The retinal VEGF level was measured by Western blot analysis. Results: Angiostatin decreased vascular leakage in the retina but not in the choroid or iris of OIR rats. This response in the retina was angiostatin dose-dependent. A significant reductions in permeability were observed at 1 and 2 days but not 3 days after the angiostatin injection. The maximal effect was observed 2 days after the injection, reducing retinal vascular permeability to 55% of that in the PBS-injected control (P<0.01, n=4). In STZ-diabetic rats, angiostatin significantly reduced permeability in the retina (20% of PBS-control, P<0.01, n=4), choroid (60% of PBS-control, P<0.01, n=4) and iris (78% of PBS-control, P<0.05, n=4). Retinal angiography showed that neovascularization and non-perfusion areas were both decreased by angiostatin. Western blot analysis showed that retinal VEGF was down-regulated in angiostatin-injected eyes. This down-regulation of VEGF by angiostatin was dose-dependent. Conclusions: Angiostatin decreases the pathological vascular permeability. This effect may be ascribed to its down-regulation of VEGF expression.

Keywords: diabetic retinopathy • retinal neovascularization • age-related macular degeneration