Mitigation of Oxygen-Induced Retinopathy in α2β1 Integrin-Deficient Mice

Abstract

PURPOSE. The a2b1 integrin plays an important but complex role in angiogenesis and vasculopathies. Published GWAS studies established a correlation between genetic polymorphisms of the a2b1 integrin gene and incidence of diabetic retinopathy. Recent studies indicated that a2-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 a2-integrin deficiency extended to the retina, using the oxygeninduced retinopathy (OIR) model for retinopathy of prematurity (ROP).METHODS. In the OIR model, wild-type (WT) and a2-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 a2-null mice were isolated and analyzed for hypoxia-induced VEGF-A expression.RESULTS. In the retina, the a2b1 integrin was minimally expressed in endothelial cells and strongly expressed in activated Müller cells. Isolated a2-null primary Müller cells demonstrated decreased hypoxia-induced VEGF-A expression. In the OIR model, a2-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 a2b1 integrin contributes to the pathogenesis of retinopathy. We describe a newly identified role for a2b1 integrin in mediating hypoxiainduced Müller cell VEGF-A production.

Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium

“…The complete revascularization of avascular areas argued against a strong anti-angiogenic activity of Gpr116, as seen in the case of severe blockade of VEGF [ 53 ]. The absence of tuft formation is, in turn, one of the more remarkable findings in comparison with previously described OIR phenotypes (such as in [ 54 ]), and seems as extensive as the A2A receptor and N-CAM mutants [ 49 ][ 50 ]. It is also the only phenotype reported to date in Gpr116 knockouts that presents a graded response, with intermediate effect in the heterozygous littermates.…”

The integrin–collagen connection – a glue for tissue repair?

“…In view of its high expression on keratinocytes and its identification on dermal fibroblasts, the finding that α2β1 was not involved in keratinocyte migration or dermal fibroblast wound closure in vivo was surprising (Parks, 2007), even though increased neoangiogenesis was observed during wound healing (Grenache et al, 2007;Zweers et al, 2007). In a more recent study, reduced pathological neovascularization in integrin α2 −/− mice was observed in a model for retinopathy (Madamanchi et al, 2014a). The absence of α2 is known to delay fibrosis and glomerular damage in experimental kidney disease models, including the Alport syndrome mouse model (Borza et al, 2012;Rubel et al, 2014).…”

IGF-1 Regulates the Extracellular Level of Active MMP-2 and Promotes Müller Glial Cell Motility

“…[63][64][65] Many human diseases, including retinopathies, have been associated with altered integrin-mediated adhesion and migration. [66][67][68] Therefore, there has been strong interest in understanding and potentially targeting integrin-mediated FIGURE 6. b1-integrin and MMP-2 colocalization is increased in MIO-M1 cells stimulated with IGF-1. The top two rows show representative images obtained by confocal microscopy.…”