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S Yamamoto, PL Gehlbach, W Xiao, T Deering, Y Oshima, K Mori, PA Campochiaro; Characterization of Double Transgenic Mice With Inducible Expression of VEGF in the Retina . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2810.
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Purpose:We have previously described mice with tetracycline-inducible (tet/on) expression of VEGF in photoreceptors, which develop neovascularization (NV) and retinal detachment (RD). In this study, we assessed the effect of different doses of doxycycline (dox) on VEGF expression and the timing of onset of breakdown of the blood-retinal barrier (BRB), NV, and RD. The reversibility of changes was also examined. Methods:Adult rhodopsin promoter (rho)/reverse tetracycline transactivator (rtTA)-tetracycline response element (TRE)/VEGF (rho/rtTA-TRE/VEGF) or interphotoreceptor retinoid binding protein promoter (IRBP)/rtTA-TRE/VEGF double transgenics were given various amounts of dox in their drinking water and then examined daily by indirect ophthalmoscopy to assess NV and RD. After identification of an optimal dox dose, the time course, at that dose, of phenotypic changes including quantitative measurement of BRB breakdown using [3H]mannitol and VEGF expression by ELISA were examined. Dose-response effects and reversibility of changes were examined. Results:At each dose of dox tested, IRBP/rtTA-TRE/VEGF had higher levels of VEGF and greater phenotypic change than that seen in rho/rtTA-TRE/VEGF mice. In the former, addition of 2 mg/ml of dox to the drinking water resulted in more rapid and severe change than that seen with other tested doses. Maximum retinal VEGF levels occurred on day 3. Breakdown of the BRB occurred on day 2 and then increased dramatically, peaking on day 3. RD first occurred in some mice on day 3. On each successive day more mice developed RD with almost all detaching by day 7. Decreased doses of dox resulted in decreased rates of RD. Withdrawal of dox resulted in regression of retinal detachment in all animals with a clear fundus view. All animals with significant cataract formation had persistent RD on sectioning. Conclusion:Dox dose-dependent, inducible expression of VEGF, results in graded severity of changes that are reversible when dox is withdrawn. Failure of RD to regress was associated with cataract formation and may indicate retina to lens contact during the period of VEGF induction.
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