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1 Department of Pediatrics, Northwestern University, Chicago, IL, USA
2 Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT, USA
3 Department of Pediatrics, State University of New York at Buffalo, Buffalo, NY, USA
* To whom correspondence should be addressed. E-mail: stephen.black{at}umontana.edu.
Similar to infants born with persistent pulmonary hypertension of the newborn (PPHN) there is an increase in circulating endothelin-1 (ET-1) and decreased cGMP-mediated vasodilation in an ovine model of PPHN. These abnormalities lead to vasoconstriction and vascular remodeling. Our previous studies have demonstrated that reactive oxygen species levels are increased in pulmonary arterial smooth muscle cells (PASMCs) exposed to ET-1. Thus, the initial objective of this study was to determine whether the development of pulmonary hypertension in utero was associated with elevated production of the reactive oxygen species (ROS) hydrogen peroxide (H2O2) and if this was associated with alterations in anti-oxidant capacity. Second we wished to determine whether chronic exposure of PASMCs isolated from fetal lambs to H2O2 would mimic the decrease in soluble guanylate cyclase expression observed in the ovine model of PPHN. Our results indicate that H2O2 levels are significantly elevated in pulmonary arteries isolated from 136 day-old fetal PPHN lambs (P< 0.05). In addition, we determined that catalase and glutathione peroxidase expression and activities remained unchanged. Also, we found that the overnight exposure of fetal PASMCs to a H2O2 generating system resulted in significant decreases in sGC expression and NO-dependent cGMP generation (P< 0.05). Finally, we demonstrated that the addition of the ROS scavenger catalase to isolated pulmonary arteries normalized the vasodilator responses to exogenous NO. As these scavengers had no effect on the vasodilator responses in pulmonary arteries isolated from age-matched control lambs this enhancement appears to be unique to PPHN. Overall our data suggest a role for H2O2 in the abnormal vasodilation associated with the pulmonary arteries of PPHN lambs.
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