Chronic Intrauterine Pulmonary Hypertension Increases Preproendothelin-1 and Decreases Endothelin B Receptor mRNA Expression in the Ovine Fetal Lung

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Endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen, is produced from its precursor, preproendothelin-1 (ppET-1), by ET-converting enzyme (ECE-1) activity. 1 Ivy DD Le Cras TD Horan MP et al. Increased lung preproET-1 and decreased ETB-receptor gene expression in fetal pulmonary hypertension. Am J Physiol. 1998; 274: L535-L541 PubMed Google Scholar Past studies have suggested that ET-1 contributes to high pulmonary vascular resistance (PVR) in the normal fetal lung and that the hemodynamic effects of ET-1 are mediated through stimulation of ETa and ETb receptors, which cause vasoconstriction and vasodilation, respectively. Increased ET-1 production may also contribute to high PVR in an experimental model of persistent pulmonary hypertension of the newborn, induced by intrauterine ligation of the ductus arteriosus (DA). In this model, closure of the DA in the late gestation fetal lamb causes progressive elevation of PVR in utero, marked right ventricular hypertrophy, hypertensive pulmonary vascular remodeling, and sustained elevation of PVR despite mechanical ventilation with high fraction of inspired oxygen after delivery. Based on past physiologic studies from our laboratory, we hypothesized that increased ET-1 production and altered ETa and ETb receptor activities contribute to the pathophysiology of this experimental model of persistent pulmonary hypertension of the newborn. To define mechanisms of altered ET-1 activity and to study further the role of ET-1 in perinatal pulmonary hypertension, we studied lung mRNA expression of ppET-1, ECE-1, and ETa and ETb receptors in normal and hypertensive fetal lambs. Total RNA was isolated from whole lung tissue in normal late gestation fetuses (135±3 days; term=147 days) and from animals with pulmonary hypertension after DA ligation for 8 days (134±4 days). Northern blot analysis was performed with cDNA probes and was normalized to the signal for 18s rRNA. We found a 71±24% increase in steady state ppET-1 mRNA (p<0.05) and a 62±5% decrease in ETb mRNA expression after DA ligation (p<0.05). ECE-1 and ETa receptor mRNA expression did not change. We conclude that chronic intrauterine pulmonary hypertension caused by DA ligation increases steady state ppET-1 mRNA and decreases ETb receptor mRNA without changing ECE-1 mRNA or ETa receptor mRNA expression. These findings suggest that both increased ET-1 production and decreased ETb receptor expression favor increased vasoconstrictor tone and contribute to high PVR in experimental neonatal pulmonary hypertension.