ALUNG February 22/2

Parker, Thomas A., D. Dunbar Ivy, Henry L. Galan, Theresa R. Grover, John P. Kinsella, and Steven H. Abman. Estradiol improves pulmonary hemodynamics and vascular remodeling in perinatal pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 278: L374–L381, 2000.—Partial ligation of the ductus arteriosus (DA) in the fetal lamb causes sustained elevation of pulmonary vascular resistance (PVR) and hypertensive structural changes in small pulmonary arteries, providing an animal model for persistent pulmonary hypertension of the newborn. Based on its vasodilator and antimitogenic properties in other experimental studies, we hypothesized that estradiol (E2) would attenuate the pulmonary vascular structural and hemodynamic changes caused by pulmonary hypertension in utero. To test our hypothesis, we treated chronically instrumented fetal lambs (128 days, term 5 147 days) with daily infusions of E2 (10 μg; E2 group, n 5 6) or saline (control group, n 5 5) after partial ligation of the DA. We measured intrauterine pulmonary and systemic artery pressures in both groups throughout the study period. After 8 days, we delivered the study animals by cesarean section to measure their hemodynamic responses to birth-related stimuli. Although pulmonary and systemic arterial pressures were not different in utero, fetal PVR immediately before ventilation was reduced in the E2-treated group (2.43 6 0.79 vs. 1.48 6 0.26 mmHg·ml21 ·min, control vs. E2, P , 0.05). During the subsequent delivery study, PVR was lower in the E2-treated group in response to ventilation with hypoxic gas but was not different between groups with ventilation with 100% O2. During mechanical ventilation after delivery, arterial partial O2 pressure was higher in E2 animals than controls (41 6 11 vs. 80 6 35 Torr, control vs. E2, P , 0.05). Morphometric studies of hypertensive vascular changes revealed that E2 treatment decreased wall thickness of small pulmonary arteries (59 6 1 vs. 48 6 1%, control vs. E2, P , 0.01). We conclude that chronic E2 treatment in utero attenuates the pulmonary hemodynamic and histological changes caused by DA ligation in fetal lambs.