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L. E. Downie, M. J. Pianta, A. J. Vingrys, J. L. Wilkinson-Berka, E. L. Fletcher; AT1R Inhibition is Retino-Protective in Retinopathy of Prematurity (ROP). Invest. Ophthalmol. Vis. Sci. 2008;49(13):2634. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
ROP is an iatrogenic retinal neovascular disease affecting premature infants. This study has characterized the effect of angiotensin II type-1 receptor (AT1R) inhibition, using valsartan, on vascular, neuronal and glial cell pathology in experimental ROP.
To induce ROP, newborn Sprague Dawley rats were exposed to an intermittent hyperoxic (80%:21% oxygen, 22:2 hours/day) environment until postnatal day (P) 11, then 7 days room air. Age-matched controls were raised in room air from P0-18. Valsartan (40 mg/kg/day) was administered systemically to one cohort of control and ROP pups from P12-P18; n=6-8 per group. The vascular response was examined immunocytochemically using retinal wholemounts and vertical sections labelled with endothelial (isolectin-B4) and pericyte (NG2, desmin) markers. Glial cells were assessed by measuring cell numbers and immunoreactivity (S100β, connexin-26 and glial fibrillary acidic protein). Pattern recognition analysis of multiple amino acids was used to classify retinal neural elements and quantify neurochemical disruptions in different neuronal populations.
ROP resulted in extensive intra-vitreal neovascularization and under-development of the deep vascular plexus. Pericyte numbers were not significantly affected, although pericyte-endothelial (desmin-IB4) interactions were impaired. Peripheral astrocyte degeneration occurred between P11 and P13, with prominent Müller cell gliosis at P18. The most prominent neural changes involved a loss of peripheral AII amacrine cells and a reduction of three INL neurochemical theme classes. Valsartan imparted a protective effect on all retinal elements. At P18, valsartan-treated ROP retinae showed significantly greater astrocyte survival, improved vascularization, reduced neovascularization and improved neuronal survival.
AT1R-signalling blockade suppressed pathological angiogenesis and protected peripheral neurons and glia. These findings support therapeutic approaches that modulate the renin-angiotensin system in ROP.
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