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L. E. Downie, M. J. Pianta, A. J. Vingrys, J. L. Wilkinson-Berka, E. L. Fletcher; Valsartan Preserves Neuronal-Glial-Vascular Relationships in Retinopathy of Prematurity (ROP). Invest. Ophthalmol. Vis. Sci. 2007;48(13):4047.
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ROP is a retinal vaso-proliferative disorder affecting premature infants. This study has characterized neuronal and glial dysfunction relative to eccentricity-based changes in the vasculature in ROP. We also assessed the effect of angiotensin II type 1 receptor (AT1R) antagonism upon retinal pathology.
ROP was induced in Sprague Dawley rats by exposure to 80±2% oxygen from postnatal (P) days 0-11, then 7 days room air. Controls were raised in room air. The AT1R antagonist valsartan (40mg/kg/day, intraperitoneal) was given to one group of control and ROP rats from P12-P18. Two further groups of control and ROP pups were sham injected (Tris Buffer, pH=8); n=6-8 per group. The vascular response was assessed by counting blood vessel profiles and by immunocytochemical localization of the endothelial cell marker isolectin-B4and the pericyte marker desmin. Glia were evaluated using glial fibrillary acidic protein, S100ß and EAAT4. Post-embedding immunocytochemistry was used to compare amino acid neurochemistry in neurons and glia.
ROP induced major changes to all retinal elements. The periphery was most affected, with a reduction in intraretinal blood vessels, intra-vitreal neovascularization, altered pericyte-endothelial interactions, reduced inner retinal thickness, neurochemical anomalies in amacrine and bipolar cells, astrocyte degeneration and Müller cell gliosis. In the mid-periphery we defined a "transition zone" in which local inner retinal blood vessels protected retinal integrity. At P18, valsartan-treated ROP pups had significantly reduced pathological neovascularization, improved physiological vascularization, more astrocytes and increased inner retinal thickness (ANOVA p<0.05) compared with shams.
This study reveals complexity in the relationship of neuronal and glial cells to the vasculature in ROP. AT1R-signalling blockade suppressed pathological angiogenesis and protected peripheral neurons and glia. These findings support therapeutic approaches that alter signalling via the renin-angiotensin system in proliferative retinopathies.
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