Transgenic Mice with Increased Expression of Vascular Endothelial Growth Factor in the Retina: A New Model of Intraretinal and Subretinal Neovascularization.

Abstract

Vascular endothelial growth factor (VEGF) has been implicated in retinal neovascularization (NV), but it has been difficult to produce retinal NV with exogenous VEGF. We investigated the effect ofincreased VEGF expression in the retina using tissue-specific, gain-of-function transgenic mice in which the bovine rhodopsin promoter is coupled to the gene for human VEGF New blood vessel formation or neovascularization (NV) is essential for normal eye development, but it can also cause severe ocular disease. In the retina, NV is associated with a number of disease processes, the most common of which is diabetic retinopathy, a major cause of new blindness in developed nations.1 Occlusion of retinal vessels leading to retinal ischemia is a feature shared by most diseases in which retinal NV occurs. This observation led to the hypothesis that the development of retinal NV is stimulated by one or more angiogenesis factors released by ischemic retina.23 Substantial effort has been devoted to identifying the factor or factors involved.

Vascular endothelial growth factor in eye disease

“…In situ hybridization analyses showed the proliferation of blood vessels to be accompanied by an induction of retinal VEGF expression only in the retinal layer effected by decreased perfusion (Pe'er et al, 1995). Also, transgenic mice with overexpression of VEGF in the photoreceptor layer develop intraretinal and subretinal neovascularization (Okamoto et al, 1997). In a single report in the literature, in situ hybridization studies of an autopsy specimen with stage 3 ROP showed increased VEGF mRNA expression in the peripheral avascular region in the ganglion cell layer and inner nuclear layer, confirming the results from the animal studies described below (Young et al, 1997).…”

Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood–retinal barrier

“…The fusion gene was purified and transgenic mice were generated as previously described. 27 Mice were screened by polymerase chain reaction (PCR) of tail DNA using an upstream primer in the TRE domain (GAC CTC CAT AGA AGA CAC CG) and a downstream primer in the ang1 domain (CCT ATG TGA GTC AGA ATG GC) that amplify a 500 bp transgenespecific product. Tail DNA was obtained by overnight digestion of a 2 mm tail segment in 0.5 mg/ml proteinase K, 10 mmol/l Tris-HCl, pH 7.5, 100 mmol/l NaCl, 20 mmol/l ethylenediaminetetraacetic acid, and 2% Triton X-100 at 551C.…”

Platelet-Derived Growth Factor-A-Induced Retinal Gliosis Protects against Ischemic Retinopathy

“…25 Mice from the V-6 line that are heterozygous for the rhodopsin/VEGF transgene develop NV that originates from the deep capillary bed of the retina and grows into the subretinal space, where it gradually spreads and enlarges. V-6 rho/VEGF mice were mated with rho/PDGF-A2 or rho/PDGF-A3 mice and, at P21, the offspring were perfused with fluorescein-labeled dextran, and retinal NV was measured on retinal flat mounts as previously described.…”