HYPOXIA-INDUCED EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR BY RETINAL CELLS IS A COMMON FACTOR IN NEOVASCULARIZING OCULAR DISEASES

BACKGROUND: It is generally assumed that unwarranted, excessive neovas cularization of the retina and iris is a direct response to a hypoxic retinal environment. Prompted by our previous findings that the potent angiogenic factor, vascular endothelial growth factor (VEGF), is hypo xia-inducible, we used in situ hybridization techniques to examine the thesis that VEGF functions as the link between retinal ischemia and a pathologic, intraocular, angiogenic response. EXPERIMENTAL DESIGN: To gain molecular access to human material representing progressive stag es of angiogenic eye diseases, in situ hybridization analysis was carr ied out on sections of whole globes enucleated at the time of ongoing neovascularization. This methodology identified cells that have up-reg ulated VEGF expression during natural progression of the indicated dis eases. A rabbit model was also used to determine whether experimentall y induced retinal ischemia leads to up-regulation of VEGF expression. RESULTS: Proliferation of vascular elements in proliferative diabetic retinopathy and neovascularization of the retina and/or iris secondary to central retinal vein occlusion, retinal detachment, and intraocula r tumors were always accompanied by induction of retinal VEGF expressi on. Furthermore, in each case, expression of VEG;F was induced only in a particular layer of the retina (either the outer nuclear layer, the inner nuclear layer, or the ganglion cell layer), matching the zones affected by impaired perfusion. In a rabbit model simulating retinal v ein occlusion, elevated levels of VEGF mRNA were detected within a few days of experimental induction of retinal ischemia, exclusively in th e ischemic region. CONCLUSIONS: VEGF may be one of the long anticipate d factors linking retinal ischemia and intraocular angiogenesis. Irres pective of the cause of retinal ischemia, sustained overproduction of VEGF by ischemic retinal cells may promote retinal and iris neovascula rization in a number of neovascular eye diseases.