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1 Pediatric Heart Lung Center and Section of Pediatric Pulmonary Medicine, University of Colorado School of Medicine, Denver, Colorado 80218; and 2 Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, California 95616
In addition to its vasodilator properties,
nitric oxide (NO) promotes angiogenesis in the systemic circulation and
tumors. However, the role of NO in promoting normal lung vascular
growth and its impact on alveolarization during development or in
response to perinatal stress is unknown. We hypothesized that NO
modulates lung vascular and alveolar growth and that decreased NO
production impairs distal lung growth in response to mild hypoxia.
Litters of 1-day-old mouse pups from parents that were heterozygous for endothelial nitric oxide synthase (eNOS) deficiency were placed in a
hypobaric chamber at a simulated altitude of 12,300 ft
(FIO2 = 0.16). After 10 days,
the mice were killed, and lungs were fixed for morphometric and
molecular analysis. Compared with wild-type controls, mean linear
intercept (MLI), which is inversely proportional to alveolar surface
area, was increased in the eNOS-deficient (eNOS 
/) mice [51 ± 2 µm (eNOS /) vs. 41 ± 1 µm (wild type); P < 0.01]. MLI was also increased in the eNOS
heterozygote (+/) mice (44 ± 1 µm; P < 0.03 vs. wild type). Vascular volume density was decreased in the eNOS /
mice compared with wild-type controls (P < 0.03). Lung
vascular endothelial growth factor (VEGF) protein and VEGF receptor-1
(VEGFR-1) protein content were not different between the study groups.
In contrast, lung VEGFR-2 protein content was decreased from control
values by 63 and 34% in the eNOS / and eNOS +/ mice,
respectively (P < 0.03). We conclude that exposure to
mild hypoxia during a critical period of lung development impairs alveolarization and reduces vessel density in the eNOS-deficient mouse.
We speculate that NO preserves normal distal lung growth during hypoxic
stress, perhaps through preservation of VEGFR-2 signaling.
pulmonary hypertension; persistent pulmonary hypertension of the newborn; lung hypoplasia; congenital diaphragmatic hernia; angiogenesis
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