Mitigation of oxygen-induced retinopathy in α2β1 integrin-deficient mice.

Madamanchi A, Capozzi M, Geng L, Li Z, Friedman RD, Dickeson SK, Penn JS, Zutter MM
Invest Ophthalmol Vis Sci. 2014 55 (7): 4338-47

PMID: 24917135 · PMCID: PMC4102391 · DOI:10.1167/iovs.14-14061

PURPOSE - The α2β1 integrin plays an important but complex role in angiogenesis and vasculopathies. Published GWAS studies established a correlation between genetic polymorphisms of the α2β1 integrin gene and incidence of diabetic retinopathy. Recent studies indicated that α2-null mice demonstrate superior vascularization in both the wound and diabetic microenvironments. The goal of this study was to determine whether the vasculoprotective effects of α2-integrin deficiency extended to the retina, using the oxygen-induced retinopathy (OIR) model for retinopathy of prematurity (ROP).

METHODS - In the OIR model, wild-type (WT) and α2-null mice were exposed to 75% oxygen for 5 days (postnatal day [P] 7 to P12) and subsequently returned to room air for 6 days (P12-P18). Retinas were collected at postnatal day 7, day 13, and day 18 and examined via hematoxylin and eosin and Lectin staining. Retinas were analyzed for retinal vascular area, neovascularization, VEGF expression, and Müller cell activation. Primary Müller cell cultures from WT and α2-null mice were isolated and analyzed for hypoxia-induced VEGF-A expression.

RESULTS - In the retina, the α2β1 integrin was minimally expressed in endothelial cells and strongly expressed in activated Müller cells. Isolated α2-null primary Müller cells demonstrated decreased hypoxia-induced VEGF-A expression. In the OIR model, α2-null mice displayed reduced hyperoxia-induced vaso-attenuation, reduced pathological retinal neovascularization, and decreased VEGF expression as compared to WT counterparts.

CONCLUSIONS - Our data suggest that the α2β1 integrin contributes to the pathogenesis of retinopathy. We describe a newly identified role for α2β1 integrin in mediating hypoxia-induced Müller cell VEGF-A production.

Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

MeSH Terms (16)

Animals Animals, Newborn Cells, Cultured Disease Models, Animal Endothelium, Vascular Ependymoglial Cells Gene Expression Regulation Integrin alpha2beta1 Mice Mice, Inbred C57BL Microscopy, Fluorescence Oxygen Polymerase Chain Reaction Retinopathy of Prematurity RNA Vascular Endothelial Growth Factor A

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