Abstract
Purpose: :
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.
Methods: :
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.
Results: :
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.
Conclusions: :
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.
Keywords: retinopathy of prematurity • neovascularization • glia