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Silke Becker, Phillippa Cottrill, Rebecca Longbottom, Karen Eastlake, Megan Jones, Hari Jayaram, G Astrid Limb; Release of pro- and anti-angiogenic factors from Müller glia cells in response to hyperoxia. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3690.
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Retinal degenerative conditions such as diabetic retinopathy and retinopathy of prematurity are characterized by alterations in tissue oxygenation, which lead to oxidative stress as well as the release of pro-angiogenic factors, resulting in ectopic blood vessel formation and traction retinal detachment. Müller glia cells have been shown to release pro-angiogenic factors in response to hypoxia, and although reactive oxygen species have been implicated in the development of neovascular retinal disease, their role on Müller glia cell release of angiogenic factors remains to be elucidated. In the present study we have investigated whether the expression of antioxidant genes and the release of pro- and antiangiogenic factors are altered in Müller glia cells in response to alterations in the ambient oxygen concentration.
MIO-M1 cells, a Müller glia cell line, were cultured for 3 or 7 days under normoxic (5% oxygen) or hyperoxic conditions (21% oxygen). Total RNA was extracted, reverse transcribed and PCR performed using specific primers for HO-1, HO-2, NQ01, SOD1 and SOD3 as well as PEDF, VEGF, VEGF receptor 2, angiopoietin-2, IGF-2. and β-actin. PCR products were examined by gel electrophoresis and were quantified by densitometric analyis.
We showed that mRNA expression of the antioxidant gene HO-1, but not for HO-2, NQ01, SOD1 or SOD3 was upregulated in cells cultured under hyperoxic conditions for 3 days. mRNA expression of the anti-angiogenic PEDF was reduced under hyperoxic conditions after 7 days, while the pro-angiogenic factors VEGF, angiopoietin-2 and IGF-2 as well as VEGF receptor 2 were shown to be upregulated after 7 days of culture in 5% oxygen.
Our findings indicate that hyperoxia induces the upregulation of the antioxidant gene HO-1 and leads to the reduced expression of the anti-angiogenic factor PEDF and the pro-angiogenic growth factors VEGF, angiopoietin-2 and IGF-2 as well as VEGF receptor 2 in Müller glia cells. The present study provides an important insight into the mechanisms that control the release of pro-angiogenic factors by Müller glia under oxidative stress, which may contribute to the development of retinal degenerative conditions associated with excessive angiogenesis such as diabetic retinopathy and retinopathy of prematurity.
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