Response of vascular endothelial growth factor and angiogenesis-related genes to stepwise increases in inspired oxygen in neonatal rat lungs

Abstract

Bronchopulmonary dysplasia is an inflammatory lung disease that afflicts preterm infants requiring supplemental oxygen and is associated with impaired pulmonary angiogenesis. We tested the hypothesis that there is a critical threshold of inspired O2 (FiO2) that alters pulmonary angiogenesis. Within 2-6 h of birth, rat pups were exposed to 10%, 21%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% FiO2 for 2 h. Mixed arterial-venous blood gases, serum and pulmonary levels of vascular endothelial growth factor (VEGF) and soluble VEGF receptor-1, and pulmonary angiogenesis gene profiles were determined. PO2 increased with hyperoxia from 35.6 ± 5.0 (range: 31.5-39.8) at 10% O2 to 108.5 ± 25.0 (range: 82.2-134.8) at 100% O2. PO2 at 21% O2 was 42.4 ± 7.3 (range: 36.8-48.1). Lung VEGF levels declined at 40%-100%. The critical PO2 associated with decreased lung VEGF was 66 mm Hg, achieved with a FiO2 of 0.4. PO2 was inversely correlated with VEGF levels in the lungs (R = -0.377; P < 0.008). Antiangiogenesis genes were robustly upregulated at 70%, predominantly in males. Data are reported as mean ± SD. A critical threshold of FiO2 affecting angiogenesis exists in immature lungs. Exposure of preterm lungs to >40% inspired O2, even for 2 h, may result in abnormal expression of biomarkers regulating lung angiogenesis.