Inhaled NO restores lung structure in eNOS-deficient mice recovering from neonatal hypoxia

We have previously shown that neonatal mice deficient in endothelial nitric oxide synthase ( eNOS(-/-)) are more susceptible to hypoxic inhibition of alveolar and vascular growth. Although eNOS is downregulated, the role of nitric oxide ( NO) during recovery after neonatal lung injury is poorly understood. We hypothesized that lung vascular and alveolar growth would remain impaired in eNOS(-/-) mice during recovery in room air and that NO therapy would augment compensatory lung growth in the eNOS(-/-) mice during recovery. Mice ( 1 day old) from heterozygous ( eNOS(+/-)) parents were placed in hypobaric hypoxia ( FIO2 = 0.16). After 10 days, pups were to recovered in room air ( HR group) or inhaled NO ( 10 parts/million; HiNO group) until 3 wk of age, when lung tissue was collected. Morphometric analysis revealed that the eNOS(-/-) mice in the HR group had persistently abnormal lung structure compared with eNOS-sufficient ( eNOS(+/+)) mice ( increased mean linear intercept and reduced radial alveolar counts, nodal point density, and vessel density). Lung morphology of the eNOS(+/-) was not different from eNOS(+/+). Inhaled NO after neonatal hypoxia stimulated compensatory lung growth in eNOS(-/-) mice that completely restored normal lung structure. eNOS(+/-) mice ( HR group) had a 2.5-fold increase in lung vascular endothelial growth factor ( VEGFR)-2 protein compared with eNOS(+/+) ( P < 0.05). eNOS(-/-) mice ( HiNO group) had a 66% increase in lung VEGFR-2 protein compared with eNOS(-/-) ( HR group; P < 0.01). We conclude that deficiency of eNOS leads to a persistent failure of lung growth during recovery from neonatal hypoxia and that, after hypoxia, inhaled NO stimulates alveolar and vascular growth in eNOS(-/-) mice.