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R.C. Symons, W.H. Xiao, Y.Y. Gong, M.E. Swaim, P.A. Campochiaro; Physiological Dissection of an Interstrain Difference in Susceptibility to Ischemic Retinopathy in Mice . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1431.
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© ARVO (1962-2015); The Authors (2016-present)
Oxygen induced ischemic retinopathy (OIIR) in mice models aspects of retinopathy of prematurity and advanced diabetic retinopathy in humans. In this OIIR, hyperoxia induced retinal vascular regression in infant mice with subsequent ischemia of the avascular retina induces pathological retinal vascular proliferation. In comparison with BALB/c mice, C57BL/6 mice develop more neovascularization in the OIIR model. In this study, we investigated the mechanism responsible for this difference.
OIIR was induced by placing the mice in a chamber with a controlled O2 concentration of 75% from post–gestational day (P) 7 –12, and then returning the mice to normoxia. Retinal avascular areas at P12 and P15 were measured from images of flat–mounted retinas after intra–cardiac fluorescein–dextran perfusion. HIF–1α levels were compared using immunoblotting. Real–time PCR was used to determine retinal mRNA transcription of vascular endothelial growth factor–A (Vegfa), Angiopoetin 2 (Agpt2), Thrombospondin–1 (Tsp1) and Platelet endothelium derived factor (Pedf) relative to expression of the S16 ribosomal protein.
Avascular area measurements at P12 were 2.7 ± 0.4 mm2 (mean ± sd) and 4.2 ± 0.4 mm2 in BALB/c and C57BL/6 mice respectively (P < 2x10–4). At P15 the measurements were 0.8 ± 0.3 mm2 and 2.9 ± 0.4 mm2 (P < 2x10–7). HIF–1α levels were qualitatively higher in C57BL/6 than BALB/c mice at P14 and P17. Pedf and Tsp1 gene expression did not differ between C57BL/6 and BALB/c mice. Vegfa and Agpt2 expression were higher in C57BL/6 mice than BALB/c mice at all time points between P14 and P17 with the greatest difference being at P16 and P17. At P16 Vegfa expression was 2.2 fold greater in C57BL/6 (P < 0.0007) and Agpt2 expression was 2.8 fold higher (P < 0.005).
Compared with BALB/c, C57BL/6 are more susceptible to hyperoxia–induced regression of the retinal vasculature, and subsequent revascularization is slower in C57BL/6. Associated with these differences are higher levels of several markers of response to hypoxia: HIF–1α protein, Vegf and Agpt2 mRNA transcription. This greater hypoxic response most likely explains the greater severity of vascular proliferation. Genetic studies are under way to determine the cause of these phenomena.
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