title: Inducible expression of vascular endothelial growth factor in adult mice causes severe proliferative retinopathy and retinal detachment.
abstract: Transgenic mice with vascular endothelial growth factor (VEGF) driven by the rhodopsin promoter (rho/VEGF mice) develop neovascularization that originates from the deep capillary bed of the retina and grows into the subretinal space. In rho/VEGF mice, VEGF expression in photoreceptors begins between postnatal days 5 and 7, the period when the deep capillary bed is developing. An important question is whether or not the developmental stage of the deep capillary bed is critical for occurrence of neovascularization. Also, although rho/VEGF mice are extremely useful for the study of ocular neovascularization, there are some applications for which the early onset of VEGF expression is a disadvantage. In this study, we used the reverse tetracycline transactivator (rtTA) inducible promoter system coupled to either the rhodopsin or interphotoreceptor retinoid-binding protein (IRBP) promoter to control the time of onset of VEGF transgene expression in photoreceptors. In the absence of doxycycline, adult double-transgenic rho/rtTA-TRE/VEGF or IRBP/rtTA-TRE/VEGF mice showed little VEGF transgene expression and no phenotype. The addition of doxycycline to the drinking water resulted in prominent transgene expression and evidence of neovascularization within 3 to 4 days. Like rho/VEGF mice, the neovascularization originated from the deep capillary bed of the retina, but it was more extensive and caused outer retinal folds followed by total retinal detachment. Real-time polymerase chain reaction and enzyme-linked immunosorbent assay demonstrated that the mice with inducible expression of VEGF that developed retinal detachment had much higher ocular levels of VEGF mRNA and protein compared to rho/VEGF mice that manifest a much milder phenotype. These data demonstrate that regardless of developmental stage of the vascular bed, increased expression of VEGF in the retina is sufficient to cause neovascularization, and high levels of expression cause severe neovascularization and traction retinal detachment. Mice with inducible expression of VEGF in the retina provide a valuable new model of ocular neovascularization.
authors.affiliation: Department of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287-9277, USA.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ohno-Matsui
authors.forename: Akira
authors.initials: A
authors.lastname: Hirose
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Jina
authors.initials: J
authors.lastname: Saikia
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Okamoto
authors.forename: Peter
authors.initials: P
authors.lastname: Gehlbach
authors.forename: Elia J
authors.initials: EJ
authors.lastname: Duh
authors.forename: Sean
authors.initials: S
authors.lastname: Hackett
authors.forename: Michelle
authors.initials: M
authors.lastname: Chang
authors.forename: Dean
authors.initials: D
authors.lastname: Bok
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012163:Retinal Detachment / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D015861:Retinal Neovascularization / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D012243:Rhodopsin / Q000235:genetics; D013223:Statistics as Topic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D000900:Anti-Bacterial Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D012243:Rhodopsin; D004318:Doxycycline