Pathological Heterogeneity of Vasoproliferative Retinopathy in Transgenic Mice Overexpressing Vascular Endothelial Growth Factor in Photoreceptors

Abstract

Retinal neovascularization is a feature shared by many disease processes including diabetic retinopathy, retinopathy of prematurity, branch retinal vein occlusion and central retinal vein occlusion, which are collectively referred to as ischemic retinopathy (Campochiaro, 2000). Retinal neovascularization is the most common cause of blindness in young diabetic patients. Investigations of the pathogenic mechanisms and therapeutic interventions for retinal neovascularization require reproducible and clinically related animal models. Currently, all diabetic models exhibit only early retinal vasculopathy after 1 or 2 years of the disease (Kondo and Kahn, 2004). The lack of retinal neovascularization in diabetic models is probably due to the natural short life span of rodents (2–3 years). In humans, DR is detected only after at least 3 years of diabetes (Dorchy et al., 2002). As angiogenesis is tightly controlled by the relative balance of stimulators and inhibitors, a shift in their balance, such as increased expression of vascular endothelial growth factor (VEGF) or decreased production of pigment epithelium-derived factor, would initiate angiogenesis (Okamoto et al., 1997; Ruberte et al., 2004; Renno et al., 2002). It is clear from literature that ischemia-induced upregulation of VEGF is a potent mediator of retinal neovascularization (Campochiaro, 2000; Miller, 1997). Animal models of retinal neovascularization have been established by oxygen-induced retinal ischemia, photodynamically-induced retinal branch vein occlusion and intravitreal implantation of VEGF sustained-release pellets (Campochiaro, 2000; Saito et al., 1997; Ozaki et al., 1997; Tolentino et al., 2002). However, retinal neovascularization in these animal models is either transient or occurs with a delayed onset.