INCREASED VASCULAR ENDOTHELIAL GROWTH-FACTOR (VEGF) AND TRANSFORMING-GROWTH-FACTOR-BETA (TGF(BETA)) IN EXPERIMENTAL AUTOIMMUNE UVEORETINITIS - UP-REGULATION OF VEGF WITHOUT NEOVASCULARIZATION

Experimental autoimmune uveoretinitis (EAU) was induced in Lewis rats and B10.A mice by immunization with S-antigen (S-Ag) to study the pote ntial roles of vascular endothelial growth factor (VEGF) and the beta( 1) and beta(2) isoforms of transforming growth factor (TGF(beta 1) sta ining for VEGF, TGF(beta 1) and TGF(beta 2)) during the progression of the disease. VEGF has been implicated as an angiogenic factor in isch emic retinopathies; however, Lewis rats developing EAU have high level s of VEGF in the retina, but no neovascularization. In the present stu dy, immunohistochemical staining for VEGF, TGF(beta 1) and TGF(beta 2) was performed on the retinas of Lewis rats developing EAU or with oxy gen-induced ischemic retinopathy. In rats immunized with S-antigen, a marked upregulation of VEGF was immunohistochemically visualized from the inner nuclear layer to the inner limiting membrane prior to blood- retinal barrier (BRB) failure and lymphocytic infiltration. VEGF is no rmally induced by hypoxia and its induction leads to neovascularizatio n. Coincident with the increase in VEGF, there was increased immunorea ctivity for TGF(beta 1) and TGF(beta 2) within the same layers of the retina. In contrast, rats with ischemic retinopathy and retinal neovas cularization showed only a modest increase in VEGF immunoreactivity, w hich is largely confined to retinal ganglion cells and inner retinal v essels, and little or no increase in TGF(beta 1) or TGF(beta 2). In ad dition, in mice developing EAU, which does not have an abrupt onset as it does in rats and may involve neovascularization, a comparable upre gulation of VEGF in the inner retina to that seen in rats developing E AU occurs with no increase in TGF(beta 1) or TGF(beta 2). Since TGF(be ta) can inhibit endothelial cell proliferation, it is likely that an i ncrease in TGF(beta) may prevent VEGF from exerting its endothelial gr owth activity in the rat EAU model, but VEGF may be operative in induc ing BRB failure. These data suggest that there is a complex interactio n among growth factors in the retina and that retinal neovascularizati on may require an imbalance between stimulatory and inhibitory factors . (C) 1998 Elsevier Science B.V. All rights reserved.