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Felicitas Bucher, Mollie Friedlander, Toshihide Kurihara, Peter D Westenskow, Edith Aguilar, Tim U Krohne, Yoshihiko Usui, Elizabeth Scheppke, Martin Friedlander; Elucidating the molecular basis for the severe hypoxia-induced proliferative retinopathy associated with dystrophin deficiency. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3395.
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© ARVO (1962-2015); The Authors (2016-present)
Recent case reports have shown that Duchenne muscular dystrophy (DMD) patients are prone to develop severe proliferative retinopathy under hypoxic stress. Panretinal photocoagulation and anti-VEGF treatment have been used to treat these patients with varying degrees of therapeutic success. The molecular basis for the development of severe retinal neovascularization associated with dystrophin deficiency is not understood. In this study, we used the oxygen-induced retinopathy (OIR) model in dystrophin deficient Mdx3cv mice to investigate the relationship between dystrophin deficiency and hypoxia-induced proliferative retinopathy.
Mdx3cv mice were used as a disease model of DMD. In the OIR model, mutant mice and littermate controls were exposed to hyperoxia (75% oxygen) from postnatal day seven (P7) to twelve (P12) and then returned to room air. Areas of vaso-obliteration (VO) and neovascularization (NV) were quantified on P17. Expression levels of VEGF isoforms and VEGF receptor- 2 were examined using qPCR, ELISA and western blots at different time points during the hypoxic phase (P12-P17). Spatial and temporal changes in local VEGF expression levels were examined using in situ hybridization. PCR arrays were employed to identify potentially dysregulated angiogenesis-related factors at P14 and P17.
Mdx3cv mice develop significantly more NV in the OIR model compared to littermate controls (p<0.01). Preliminary data suggest that at P17 (when NV is maximal), mRNA levels for the VEGF-isoforms 120, 164 and 180 are uniformly down-regulated by 18% to 38%. VEGF receptor- 2 mRNA and protein expression levels were also reduced by 35% to 42% in mutant mice compared to littermate controls. However, preliminary data also suggests that the same VEGF isoforms might be upregulated during the early hypoxic phase around P14.
Our data suggest that the hypoxia-induced neovascularization in Mdx3cv mice may be due to a temporally dysregulated VEGF gradient. RNA arrays and in situ hybridization will yield more information about local and global regulation of VEGF and other angiogenic factors under hypoxic stress in dystrophin deficient mice. The results of these experiments may be used to re-evaluate the use of anti-VEGF treatments and to develop novel therapies for proliferative retinopathy in DMD patients.
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