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Megan E. Capozzi, Bobby Madamanchi, Ling Geng, Richard Friedman, Zhengzhi Li, Mary M. Zutter; Genetic Deletion Of The α2β1 Integrin Protects Against Neovascularization By VEGF Modulation In A Mouse Model Of Oxygen-Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2540.
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The α2β1 integrin, a cell-surface collagen receptor, has been implicated in mediating growth factor signaling in angiogenesis. We hypothesize that α2β1 integrin may interact with VEGF to produce a neoangiogenic phenotype. Therefore, we investigated the effect of genetic manipulation of α2β1 integrin on induction of VEGF and development of neovascularization (NV) in a mouse model of oxygen-induced retinopathy (OIR).
An OIR mouse model was used to determine the effect of α2β1 on NV. Eyes from OIR and room air controls of α2β1 wild type (α2WT) and α2β1 knockout (α2KO) mice were enucleated and sectioned on postnatal day 18 (P18). Localization of the α2β1 integrin was analyzed by immunohistochemistry. Retinas were collected following OIR on P13 to measure VEGF expression by qRT-PCR and VEGF secretion by ELISA. Primary cultures of muller cells were isolated from α2WT and α2KO mice, treated in normoxia or hypoxia for 24 hours, and the level of VEGF secreted into the media measured by ELISA.
α2β1 integrin was strongly expressed in a pattern consistent with muller cell distribution and moderately in endothelial cells. Expression was upregulated in response to OIR treatment. Following OIR, on P12 the α2KO exhibited a 32% decrease (p = 0.0002) of avascular area and on P17 caused a 49% decrease (p = 0.0069) of NV compared to WT controls. The OIR exposed α2KO exhibited a 39% decrease (p = 0.02) of VEGF expression and a 41% decrease (p = 0.0006) of VEGF secretion compared to the α2WT on P13. VEGF secretion was consistent between α2WT and α2KO muller cells in normoxia. In hypoxia, VEGF secretion was decreased by 46% (p = 0.01) in α2KO compared to α2WT muller cells.
This study suggests that the α2β1 integrin is an important mediator of VEGF induction by muller cells. Additionally, genetic deletion of the α2β1 integrin exerts a protective effect against the development of retinal NV. Therefore, α2β1 may serve as a valuable therapeutic target in treating pathological angiogenesis.
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