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1 Pediatric Hearl Lung Center, Department of Pediatrics, University of Colorado Health Science Center and The Children's Hospital, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: anette.kunig{at}uchsc.edu.
Impaired angiogenesis due to inhibition of VEGF signaling decreases alveolar and vessel growth in the developing lung, suggesting that impaired VEGF signaling may contribute to decreased lung growth in bronchopulmonary dysplasia (BPD). Whether chronic treatment with exogenous VEGF improves lung structure in experimental models of BPD is unknown. The purpose of this study was to determine whether VEGF treatment would enhance alveolarization in infant rats after exposure to neonatal hyperoxia. Two day old Sprague Dawley rat pups were placed into a hyperoxia chamber (FiO2, 0.75) or room air for 12 days. At 14 days, rat pups were randomized to daily treatment with recombinant human VEGF 165 (rhVEGF; 20 µg/kg) im or vehicle (saline; controls). On day 22, rats were killed, and the heart and lungs were collected for study. Morphometric analysis was assessed by measurements of radial alveolar counts (RAC), mean linear intercepts (MLI), and skeletonization by standard techniques. In comparison with room air controls, hyperoxia decreased RAC (6.1 ± 0.4 vs. 11.3 ± 0.4; p < 0.0001), increased MLI (59.2 ± 1.8 vs. 44.0 ± 0.8; p < 0.0001), decreased the number of nodal points per high power field (447 ± 14 vs. 503 ± 12; p<0.0004), and decreased vessel density (11.7 ± 0.3 vs. 18.9 ± 0.3; p<0.001) which persisted despite recovery in room air. In comparison with hyperoxic controls, rhVEGF treatment after hyperoxia increased RAC (11.8 ± 0.5; p< 0.0001), decreased MLI (42.2 ± 1.2; p < 0.0001), increased nodal point density (502 ± 7; p<0.0005), and increased vessel density (23.2 ± 0.4 vessels/hpf; p<0.001).We conclude that exposure of neonatal rats to hyperoxia impairs alveolarization and vessel density which persists despite recovery in room air, and that treatment with rhVEGF during the recovery period enhanced vessel growth and alveolarization in infant rats. We speculate that persistent abnormalities of lung structure after hyperoxia may be partly due to impaired VEGF signaling.
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