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R. Rota, R. Ciarapica, F. Verginelli, L. Raimondi, P. Hannaert; Reduced Retinal Neovascularization in ROP Mice After Cyclosporin A Intravitreal Injection. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3420.
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Recently it has been shown that Cyclosporin A (CsA) inhibits VEGF-induced corneal angiogenesis. This effect is related to CsA-mediated decrease in Cyclooxygenase 2 (Cox2) expression that is induced by VEGF. Further, CsA is one of the most potent inhibitor of the opening of the mitochondrial permeability transition pore (PTP) in response to reactive oxygen species (ROS). ROS stimulate endothelial cell activation and angiogenesis and they are produced during ROP. In this preliminary study we evaluated whether CsA injection reduces ischemia-induced retinal neovascularization.
Newborn mice were exposed to 75±1% O2 from the postnatal day 7 (P7) to day 12 (P12) to induce retinopathy of prematurity (ROP). At P12 animals were intravitreally injected in the left eye with 1µl of CsA (1µM). The right eye was injected with vehicle. At P12 and at P18 mice from both ROP and controls (not oxygen-treated) were perfused through the left ventricle with fluorescein isothiocyanate-dextran (2 x 106 molecular weight) 50 mg/ml in PBS. Six animals for each experimental group were investigated. The severity of neovascularization was quantified in flat-mounted retinas dividing each retinal quadrant into three equal parts (clock hours) and each clock hour was scored for the presence of neovascular growths, as tufts, ridges or capillary clumps. Thus, each retina could have a score from 0 to 12.
As expected, P12 ROP retinas mice showed a posterior avascular area compared to retinas from control animals. CsA injection decreased retinal neovascularization in 6/6 P18 ROP retinas down to 47.7% of neovascular score compared to that of retinas injected with vehicle (5.3±1.1 vs 11.1±0.5 neovascular score; p<0.001).
These preliminary results show that intravitreal injection of CsA inhibits hyperoxia/hypoxia-induced retinal neovascularization. Further experiments are in course to evaluate the effect of CsA on hyperoxia response in vivo, and the contributions of mitochondrial PTP and ROS in vivo and in vitro. In parallel, we initiated the stepwise integration of our data into an in silico model, using systems biology tools and concepts, in order to explore dynamic interactions among differentiation, survival and apoptosis pathways in endothelial cells.
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