VASCULAR ENDOTHELIAL GROWTH-FACTOR VASCULAR-PERMEABILITY FACTOR IS TEMPORALLY AND SPATIALLY CORRELATED WITH OCULAR ANGIOGENESIS IN A PRIMATE MODEL

Ischemia often precedes neovascularization. In ocular neovascularizati on, such as occurs in diabetic retinopathy, a diffusible angiogenic fa ctor has been postulated to be produced by ischemic retina and to lead to neovascularization of the retina, optic nerve, or iris. However, n o angiogenic factor has been conclusively identified that satisfies th is hypothesis. Vascular endothelial growth factor/vascular permeabilit y factor, hereafter referred to as VEGF, is a likely candidate for an ocular angiogenic factor because it is a secreted mitogen, specific fo r endothelial cells, and is upregulated by hypoxia. We investigated th e association of VEGF with the development of experimental iris neovas cularization in the cynomolgus monkey. Following ther production of re tinal ischemia by laser occlusion of all branch retinal veins, VEGF wa s increased in the aqueous fluid, and the aqueous VEGF levels changed synchronously and proportionally with the severity of iris neovascular ization. Northern analysis and in situ hybridization revealed that VEG F messenger RNA is upregulated in the ischemic retina. These observati ons support the hypothesis that ocular neovascularization is regulated by a diffusible factor and identify VEGF as a likely candidate for a retina-derived vascular permeability and angiogenesis factor in vivo.