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T. Hisatomi, S. Nakao, K. Noda, T. Nakazawa, S. Zandi, L. Almulki, Y. Ito, A. Hafezi-Moghadam, T. Ishibashi, J. W. Miller; The Inhibition of Apoptosis Increases Neovascularization and Retards Regression in the Choroid and Cornea Neovascularization. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5983.
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The neovascularization and its regression play important roles in various aspects, such as corneal injury or age-related macular degeneration (AMD). In choroidal neovascularization (CNV), infiltration of inflammatory cells and endothelial cells into the laser-injured site occurs early in CNV development, but these cells gradually diminish over time. Apoptotic cell death may be involved, but the mechanism remains unclear. We investigated cellular apoptosis in laser injury CNV and VEGF-induced corneal neovascularization.
To elucidate the role of apoptosis in CNV, we quantified CNV formation in wild type (WT) and apoptosis inducing factor (AIF) deficient mice (AIF-/Y). CNV was induced by laser photocoagulation with 532nm, 150mW, 100msec, 50µm settings. Eyes were enucleated at 1, 2, 4, and 12 weeks of age and were analyzed using immunohistochemistry, TUNEL, transmission electron microscopy (TEM), RT-PCR and western blotting. To test macrophage apoptosis, peritoneal macrophages induced by thioglycollate medium were collected from AIF-/Y and WT mice and cultured under starved conditions for 24 hours. Corneal neovascularization was induced using a VEGF-soaked gel implantation in a corneal micropocket in WT and AIF-/Y mice.
AIF mutant mice have greater numbers of circulating leukocytes in peripheral blood. CNV size was increased in AIF-/Y mice compared to WT at 2, 4, 12 weeks after laser induction. Following laser injury, inflammatory and endothelial cell apoptosis detected by TUNEL was significantly lower in AIF deficient mice when compared to WT at 4 weeks. The AIF-/Y peritoneal macrophages showed less apoptosis compared to WT in culture under starved conditions. Corneal neovascularization was also more extensive in AIF mutant mice compared to WT.
Mice lacking AIF show persistence of inflammatory and endothelial cells at both the laser-injury site and VEGF-implant site. Our data suggest that apoptosis plays an important role in laser-induced neovascularization, and therapeutic modulation of apoptosis via AIF may offer a new target for the treatment of pathologic neovascularization.
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