Decreased endothelial nitric oxide synthase (eNOS) may contribute to the high pulmonary vascular resistance (PVR) which characterizes persistent pulmonary hypertension of the newborn (PPHN). In experimental PPHN produced by ductus arteriosus (DA) ligation in fetal lambs, eNOS mRNA, protein, and activity are reduced. Because E2 upregulates eNOS in several experimental settings, we hypothesized that estradiol treatment would attenuate the hemodynamic and histologic changes of pulmonary hypertension (PH), and that this effect may be mediated by upregulation of eNOS. We studied the effects of chronic E2 treatment of late gestation (126-128 d; term=147 d) fetal lambs. Immediately following DA ligation and placement of catheters in the main pulmonary artery (MPA) and aorta, fetal lambs were treated with daily infusion of E2 (10 mcg; n=6) or saline (ctrl; n=5) in the MPA. Eight days after the initial surgery, a left pulmonary artery (LPA) flow transducer was placed and lambs were then delivered and mechanically ventilated with FiO2=1.0. Mean pulmonary artery pressure inutero was not different between groups(73±7 vs. 79±3 mm Hg, day 8; E2 vs. ctrl). At delivery, E2 animals had lower PVR, better oxygenation, and higher LPA flow(table; *=p<0.05, E2 vs. ctrl).

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E2 treatment decreased muscularization of small pulmonary arteries (< 100μm) as measured by wall thickness as a fraction of external diameter(p<0.01). However, lung eNOS protein was not different between groups by western blot. We conclude that E2 improves pulmonary hemodynamics at delivery and attenuates the structural vascular changes in experimental PH but does not increase eNOS protein. We speculate that the protective effect of E2 is exerted through an alternative mechanism.