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1 Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Denver, CO, USA
2 Pulmonary Medicine, University of South Alabama, Mobile, AL, USA
* To whom correspondence should be addressed. E-mail: vivek.balasubramaniam{at}uchsc.edu.
Growth and development of the lung normally occurs in the low oxygen environment of the fetus. The role of this low oxygen environment on fetal lung endothelial cell growth and function is unknown. We hypothesized that low oxygen tension during fetal life enhances pulmonary artery endothelial cell (PAEC) growth and function, and that NO production modulates fetal PAEC responses to low oxygen tension. To test this hypothesis, we compared the effects of fetal (3%) and room air (RA) oxygen tension on fetal PAEC growth, proliferation, tube formation and migration in the presence and absence of the NOS inhibitor, nitro-L-arginine (LNA), and a NO donor, S-nitroso-N-acetylpenicillamine (SNAP). In comparison with fetal PAEC grown in RA, 3% O2 increased tube formation by over 2-fold (p<0.01). LNA treatment reduced tube formation in 3% O2, but had no affect on tube formation in RA. Treatment with SNAP increased tube formation during RA exposure to levels observed in 3% O2. Exposure to 3% O2 for 48 hours attenuated cell number (by 56%) and treatment with LNA reduced PAEC growth by 44% in both RA and 3% O2. We conclude that low oxygen tension enhances fetal PAEC tube formation, and that NO is essential for normal PAEC growth, migration and tube formation. Further, we conclude that in fetal cells exposed to the relative hyperoxia of room air, 21% O2, NO overcomes the inhibitory effects of the increased oxygen allowing normal PAEC angiogenesis and branching. We speculate that NO production maintains intrauterine lung vascular growth and development during exposure to low O2 in the normal fetus. We further speculate that NO is essential for pulmonary angiogenesis in fetal animal exposed to increased oxygen tension of room air, and impaired endothelial NO production may contribute to the abnormalities of angiogenesis see in infants with BPD.
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