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Chintan Patel, Wenbo Zhang, Modesto Rojas, Zhimin Xu, Steven E. Brooks, R. W. Caldwell, Ruth B. Caldwell; Up-regulation Of The Endothelin System In A Mouse Model Of Retinopathy Of Prematurity. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3990.
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© ARVO (1962-2015); The Authors (2016-present)
Retinopathy of prematurity (ROP) is a potentially blinding disease that affects preterm babies. ROP is thought to occur due to relative hyperoxia of the extra-uterine environment. This results in constriction and obliteration of the immature vessels, leading to retinal ischemia and vitreo-retinal neovascularization (VR-NV). The endothelin (ET) system is reported to be activated by ischemia in other tissues. Components of the ET system include the vasoactive ET peptides and their receptors ETA and ETB. ET-1 and 2 and ETA and B are present in retinal blood vessels, photoreceptors and glial cells. Activation of the retinal ET system has been reported following light-induced injury and retinal detachment. In this study, we tested the hypothesis that the ET system is activated in a mouse model of ROP.
Mice were exposed to 75% oxygen from postnatal day P7 to P12, returned to room air from P12-P17, followed by hyperoxia-treatment (HT) before or after the onset of VR-NV, which reverses VR-NV and promotes vascular repair (Brooks et al., ARVO, 2011). A gene array analysis was performed using retinas of oxygen-induced retinopathy (OIR) and control mice at P17. Results were verified by using quantitative PCR and immunohistochemistry.
A whole genome array analysis revealed that the expression of 636 genes was significantly up-regulated while 138 genes was down-regulated. Amongst the up-regulated genes, the fold change of ET-2 and ETA receptor mRNA was the most prominent. This change was confirmed by quantitative PCR analysis, which revealed a large increase in mRNA of ET-2 (~370 fold) as well as a significant increase of ET-1 (~2 fold) and ETA receptor (~3 fold) in the retinas of OIR mice at P17 compared to the age-matched control mice. These expression levels were normalized by the HT. Similarly, a time-dependent increase of mRNA of ET-1, 2 and ETA receptor was also observed in OIR retinas from P12-P17. Further immunohistochemical analysis showed significant increases in ETA receptor protein expression in the OIR retinas. ETA was distributed across all layers of the retina and co-localized with blood vessels, astrocytes and Muller cells. In control mice, ETA was expressed mainly in outer nuclear layer.
ET-2 and ETA are both strongly expressed in retinas of the mouse model of ROP and expression of these genes is completely normalized by HT. Activation of the ETA receptor may cause retinal vascular injury, glial cell activation and VR-NV during ROP. Hence, blockade of the ETA receptor may prove to be an effective therapy for ROP.
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