Macular edema is a major cause of visual loss in several ocular disorders. While vascular leakage in or near the macula causes visual loss, there is usually widespread breakdown of the blood-retinal barrier (BRB), often with no accompanying pathological changes in the retinal vascular endothelium or the retinal pigmented epithelium. This suggests that soluble mediators play a role in the breakdown of the BRB. Our long-term objective is to identify mediators that are involved and develop therapies for macular edema. There are several lines of evidence that have implicated prostaglandins in the development of macular edema, but there is also evidence that suggests that they are not the only mediators involved. Another possible candidate is vascular endothelial growth factor (VEGF). VEGF is a potent stimulator of vascular permeability in several organs and may also promote vascular leakage in the retina. VEGF has been implicated as a possible angiogenesis factor in ischemic retinopathies, but our preliminary data suggest that it may also contribute to macular edema in ischemic retinopathies and in other disease processes as well. VEGF immunoreactivity is increased in eyes with macular edema due to several disease processes and in the retinas of rats with experimental autoimmune uveoretinitis (EAU). In both instances, there is vascular leakage with no neovascularization. VEGF induces vascular leakage at very low concentrations, while neovascularization may require higher concentrations or an induction of VEGF receptors. In this proposal, we will examine the expression of VEGF and its receptors in retinal disorders with and without neovascularization and in experimental models of ischemic retinopathy and uveitis by immunohistochemistry, in situ hybridization, and Northern blots. We will determine the effects of VEGF on the blood-retinal barrier by electron immunocytochemical staining for albumin in rabbits after intraocular injection of VEGF and in transgenic mice with overexpression of VEGF. We will determine if VEGF antagonists prevent breakdown of the flood-retinal barrier in models of ischemic retinopathy and EAU. We will also examine possible interactions between VEGF and other potential mediators of macular edema including prostaglandins, interleukin 1-beta, and tumor necrosis factor-alpha. The possibility that some of their effects on the BRB occur through induction of VEGF will be examined using VEGF antagonists. This proposal could provide important new information concerning the pathogenesis of macular edema and provide new avenues for therapeutic intervention.
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