Increased lung preproET-1 and decreased ETB-receptor gene expression in fetal pulmonary hypertension

1 Pediatric Heart Lung Center and Sections of Pediatric Cardiology and 2 Pediatric Pulmonary Medicine, University of Colorado School of Medicine and The Children's Hospital, Denver, Colorado 80218 Endothelin (ET)-1, a potent vasoconstrictor and smooth muscle mitogen, is produced from its precursor, preproET-1, by endothelin-converting enzyme (ECE)-1 activity. ET-1 may bind to two receptors, ET A and ET B , that mediate vasoconstriction and vasodilation in the ovine fetal lung, respectively. ET-1 contributes to high pulmonary vascular resistance in experimental perinatal pulmonary hypertension induced by ligation of the ductus arteriosus in the fetal lamb. Physiological studies in this model have demonstrated enhanced ET A - and diminished ET B -receptor activities and a threefold increase in lung immunoreactive ET-1 protein content. We hypothesized that increased ET production and an imbalance in receptor expression would favor vasoconstriction and smooth muscle cell hypertrophy in pulmonary hypertension and may be partially due to alterations in gene expression. To test this hypothesis, we studied lung mRNA expression of preproET-1, ECE-1, and the ET A and ET B receptors in normal and hypertensive fetal lambs. Total RNA was isolated from whole lung tissue in normal late-gestation fetuses (135 ± 3 days; 147 days = term) and from animals with pulmonary hypertension after ductus arteriosus ligation for 8 days (134 ± 4 days). Ductus arteriosus ligation increased right ventricular hypertrophy [control 0.56 ± 0.02 vs. hypertension 0.85 ± 0.05; right ventricle/(left ventricle + septum); P