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Departments of 1 Pediatrics and 2 Obstetrics and Gynecology, Sections of Neonatology, Cardiology, Pulmonology and Critical Care Medicine, Pediatric Heart Lung Center, University of Colorado School of Medicine, Denver, Colorado 80218
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 = 147 days) with daily infusions of
E2 (10 µg; E2 group, n = 6) or saline (control group,
n = 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 ± 0.79 vs. 1.48 ± 0.26 mmHg · ml
1 · 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 ± 11 vs. 80 ± 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 ± 1 vs. 48 ± 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.
pulmonary circulation; persistent pulmonary hypertension of the newborn; fetus; lamb
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