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William D. Eldred, Vanessa Hill, Jan Blom, James D. Akula, Tara L. Favazza, Nan Zhang; Modulation Of The Adrenomedullin/nitric Oxide Signaling Pathway In Oxygen-induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3994.
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© ARVO (1962-2015); The Authors (2016-present)
Retinopathy of prematurity (ROP) is triggered when the delicately balanced developmental interplay of retinal neurons to their vasculature is disrupted by supplemental oxygen. Though the clinical hallmark of ROP is abnormal retinal vasculature, electroretinographs (ERGs) reveal neuronal pathology in the retina. Newborn rats subjected to fluctuating high and low oxygen levels for the first two postnatal weeks exhibit changes in retinal vasculature and neuronal function similar to those seen in ROP. An adrenomedullin(ADM)/nitric oxide(NO) signaling pathway has been implicated in the pathology of diabetic retinopathy (DR), another neurovascular retinal pathology. This study was done to determine if the ADM/NO signaling pathways are likewise altered in ROP.
Newborn Sprague-Dawley rats, with their dam, were either placed in an environment where oxygen levels fluctuated between 50% and 10% every 24 hours for two weeks (to induce retinopathy), or reared in room air (21% oxygen) as controls. ERGs were obtained at P15-16. Following ERG, pups were sacrificed and immunocytochemistry (ICC) was used to examine changes in levels of ADM, neuronal nitric oxide synthase (nNOS), and the calcium-binding protein calretinin, in both the ROP and control rats.
The ERGs showed decreased receptor and postreceptor retinal function in the ROP rats; the oscillatory potentials (OPs), which originate in significant part in amacrine and ganglion cells, were especially attenuated. The ICC showed that, relative to control, ROP retinas had: decreases in ADM-like immunoreactivity (ADM-LI) in somata in the ganglion cell and inner nuclear layers, and a reduction of diffuse ADM-LI in the inner plexiform layer; increased numbers of amacrine cells with nNOS-LI; and stronger calretinin-LI in specific strata in the inner plexiform layer.
Although the ADM/NO signaling pathway is altered in ROP, it is different from what occurs in diabetic retinopathy. In ROP, it is possible the increases in calretinin, a calcium binding protein, lower the calcium-stimulated activation of nNOS, which is compensated by making more nNOS. It is also possible that, since ADM can activate nNOS, the increased nNOS is a compensation for the decrease in ADM activated nNOS. The increased levels of nNOS-LI in ROP may underlie the neuronal pathology. Further exploration of the ADM/NO signaling pathway will be necessary to establish its role in ROP and its relationship to the neural pathology.
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