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1 Departments of Pediatrics and Molecular Pharmacology, Northwestern University, Chicago, IL, USA
2 Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
3 Departments of Physiology, State University of New York at Buffalo, Buffalo, NY, USA
* To whom correspondence should be addressed. E-mail: r-steinhorn{at}northwestern.edu.
At birth, the transition to gas breathing requires the function of endothelial vasoactive agents. We investigated the function of endothelial nitric oxide synthase (NOS) in pulmonary artery vessels and endothelial cells isolated from fetal and young (4-week) sheep. We found greater relaxations to the NOS activator A23187 in 4-week compared to fetal vessels, and that the NOS inhibitor L-NA blocked relaxations in both groups. Relaxations in 4-week vessels were not blocked by an inhibitor of soluble guanylate cyclase, ODQ, but were partially blocked by catalase. We therefore hypothesized that activation of eNOS produced reactive oxygen species in 4-week but not fetal PA. To address this question, we studied NO and superoxide production by endothelial cells at baseline and following NOS stimulation with A23187, VEGF and laminar shear stress. Stimulation of NOS induced phosphorylation at Serine 1177, and this event correlated with an increase in NO production in both ages. Upon stimulation of eNOS, fetal PAEC produced only NO. In contrast 4-week old PAEC produced superoxide in addition to NO. Superoxide production was blocked by L-NAME but not by apocynin (an NADPH oxidase inhibitor). L-Arginine increased NO production in both cell types but did not block superoxide production. HSP90:eNOS association increased upon stimulation, and did not change with developmental age. Cellular levels of total and reduced biopterin were higher in fetal vs. 4-week cells. Sepiapterin (a BH4 precursor) increased basal and stimulated NO levels and completely blocked superoxide production. We conclude that the normal function of eNOS becomes uncoupled after birth, leading to a developmental adaptation of the pulmonary vascular system to produce oxygen species other than nitric oxide. We speculate this may be related to cellular production and/or maintenance of tetrahydrobiopterin levels.
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