UP-REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IN ISCHEMIC AND NONISCHEMIC HUMAN AND EXPERIMENTAL RETINAL DISEASE

Vascular endothelial growth factor (VEGF) is induced by hypoxia and it has been implicated in the development of iris and retinal neovascula rization (NV) in ischemic retinopathies in which it has been suggested that Muller cells are responsible for increased VEGF production. VEGF , however, is also known to be a potent mediator of vascular permeabil ity in other tissues and may perform this function in retina. Immunohi stochemical staining for VEGF was performed on a variety of human and experimental ischemic and non-ischemic ocular disorders in which blood retinal barrier (BRB) breakdown is known to occur to determine if the re is an upregulation of VEGF in these conditions. We found increased VEGF immunoreactivity in ganglion cells of rats with oxygen-induced is chemic retinopathy and in ganglion cells, the inner plexiform layer, a nd some cells in the inner nuclear layer of rats with experimental aut oimmune uveoretinitis (EAU), in which there was no identifiable ischem ia or NV. In rats with EAU, VEGF staining intensity increased from 8 t o 11 days after immunization, coincident with BRB failure. These resul ts were confirmed using two distinct anti-VEGF antibodies and by immun oblot and the immunohistochemical staining was eliminated by pre-incub ating the antibodies with VEGF peptide. VEGF staining was also increas ed in the retina and iris of patients with ischemic retinopathies, suc h as diabetic retinopathy and retinal vascular occlusive disease, and in patients with disorders in which retinal ischemia does not play a m ajor role, such as aphakic/pseudophakic cystoid macular edema, retinob lastoma, ocular inflammatory disease or infection, and choroidal melan oma. VEGF was primarily localized within retinal neurons and retinal p igmented epithelial cells in these cases. In addition or in associatio n with its role of inducing NV, VEGF may contribute to BRB breakdown o f in a variety of ocular disorders and blockage of VEGF signaling may help to reduce some types of macular edema.