Abstract
Purpose: :
Aberrant angiogenesis and oxidative stress are hallmarks of oxygen-induced retinopathy (OIR). Incremental hyperoxia and the range of PO2 that affects ocular angiogenesis and oxidative stress are unknown. We tested the hypothesis that there is a critical threshold of inspired O2 that influences ocular biomarkers of angiogenesis and oxidative stress in the newborn rat.
Methods: :
Within 2-6 hours of birth, 10 groups of rat pups (n=16 pups/group) were exposed to stepwise increases in inspired O2 (10%, 21%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) for 2 hours. Immediately following exposure, the pups were euthanatized and mixed arterial-venous blood gases were determined. Levels of VEGF, sVEGFR-1 (an endogenous VEGF trap), IGF-I, and 8-iso-PGF2α (a reliable marker for oxidative stress) were determined using ELISA.
Results: :
Birth weights were comparable among the groups. Mixed venous-arterial PO2 (mmHg) increased with increasing hyperoxia from 35.6±5.0 at 10% O2 (range: 31.5-39.8) to 108.5±25.0 at 100% O2 (range: 82.2-134.8). Mixed venous-arterial PO2 at 21% O2 was 42.4±7.3 (range: 36.8-48.1). At 10% O2, VEGF levels (111.5±22.0 pg/mg protein) were significantly higher than that at 21% (41.7±7.2, p<0.01), 30% (43.3±5.8, p<0.05), 80% (45.2±17.0, p<0.05), 90% (49.8±11.0, p<0.05), and 100% (46.8±8.3, p<0.05). A non-significant decrease in sVEGFR-1 was noted at 70% to 100% (92.4±11.7 to 94.6±14.0 pg/mg protein) vs. 10% to 60% (range: 136±37.5 to 239.8±48.1). IGF-I levels were significantly higher at 70% (385.5±64.2 ng/mg protein) than 80% (169.3±11.1, p<0.05), 90% (174.1±17.3, p<0.05) and 100% (144.0±27.2, p<0.01). Similar increases in 8-iso-PGF2α occurred at 70% (671.7±110.5 pg/mg protein, p<0.05), 80% (708.4±106.4, p<0.05), 90% (689.4±92.8, p<0.05), and 100% (672.9±±79.2, p<0.05) vs. 21% (290.7±40.5). Linear regression analysis revealed a significant correlation between PO2 and 8-isoPGF2α (r=0.26; p<0.001). Data are mean±SEM.
Conclusions: :
Data suggests that a critical threshold of inspired O2 exerts adverse effects on ocular biomarkers for angiogenesis and oxidative stress. Exposure of the immature eyes to >70% O2 for at least 2 hours may lead to pathogenic neovascularization.
Keywords: hypoxia • oxidation/oxidative or free radical damage • vascular endothelial growth factor