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H. Nambu, R. Nambu, Y. Oshima, E. Duh, S.F. Hackett, D.J. Zack, P.A. Campochiaro; Angiopoietin 1 (Ang1) Decreases Ocular Neovascularization (NV) and VEGF-Induced Breakdown of the Blood-Retinal Barrier (BRB) . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2901.
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Purpose: To investigate the role of ang1 in the retina. Methods: Tetracycline response element (TRE)/murine ang1 (TRE/ang1)transgenic mice were generated and crossed with reverse tetracycline transactivator(rtTA)/rhodopsin promoter (rtTA/rho) or rtTA/CMV promoter (rtTA/CMV) mice to generate double transgenics. Expression of ang1 was evaluated by RT-PCR and immunohistochemistry. Mice with doxycycline (dox)-inducible ubiquitous expression of ang1 (rtTA/CMV-TRE/ang1) or dox-inducible expression of ang1 in the retina (rtTA/rho-TRE/ang1) were used to investigate the effect of increased expression of ang1 on ischemic retinopathy, choroidal NV (CNV), and VEGF-induced breakdown of the BRB. Results: Oxygen-induced ischemic retinopathy was generated using litters of newborn rtTA/CMV-TRE/ang1 mice treated with dox or single hemizygous controls. Dox-treated double transgenics had increased ang1 mRNA and protein in the retina and significantly less retinal NV than controls. Adult rtTA/CMV-TRE/ang1 mice with laser-induced rupture of Bruch's membrane that were treated with 2 mg/ml of dox in their drinking water had significantly smaller areas of CNV at rupture sites than controls. Adult rtTA/rho-TRE/ang1 mice were given 2 mg/ml of dox in drinking water for 2 weeks and then received an intravitreous injection of 1 ml of 10-6 M VEGF as did controls. Six hours after injection, the integrity of the BRB was quantitatively assessed using [3H]mannitol as tracer. Mice with dox-induced expression of ang1 had significantly less breakdown of the BRB. Conclusions: Increased expression of ang1 in the retina suppresses the development of ischemia-induced retinal NV, CNV at Bruch's membrane rupture sites, and VEGF-induced breakdown of the BRB. These data suggest that increasing expression of ang1 in the retina provides a potential strategy for treatment of macular edema and retinal neovascularization in patients with ischemic retinopathies, or prevention of CNV in high-risk AMD patients.
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