Developmental changes in endothelin expression and activity in the ovine fetal lung

Mechanisms that regulate endothelin (ET) in the perinatal lung are complex and poorly understood, especially with regard to the role of ET before and after birth. We hypothesized that the ET system is developmentally regulate d and that the balance of ETA and ETB receptor activity favors vasoconstric tion. To test this hypothesis, we performed a series of molecular and physi ological studies in the fetal lamb, newborn lamb, and adult sheep. Lung pre proET-1 mRNA levels, tissue ET peptide levels, and cellular localization of ET-1 expression were determined by Northern blot analysis, peptide assay, and immunohistochemistry in distal lung tissue from fetal lambs between 70 and 140 days (term = 145 days), newborn lambs, and ewes. Lung mRNA expressi on for the ETA and ETB receptors was also measured at these ages. We found that preproET-1 mRNA expression increased from 113 to 130 days gestation. W hole lung ET protein content was highest at 130 days gestation but decrease d before birth in the fetal lamb lung. Immunolocalization of ET-1 protein s howed expression of ET-1 in the vasculature and bronchial epithelium at all gestational ages. ETA receptor mRNA expression and ETB receptor mRNA incre ased from 90 to 125 and 135 days gestation. To determine changes in activit y of the ETA and ETB receptors, we studied the effect of selective antagoni sts to the ETA or ETB receptors at 120, 130, and 140 days of fetal gestatio n. ETA receptor-mediated vasoconstriction increased from 120 to 140 days, w hereas blockade of the ETB receptor did not change basal fetal pulmonary va scular tone at any age examined. We conclude that the ET system is developm entally regulated and that the increase in ETA receptor gene expression cor relates with the onset of the vasodilator response to ETA receptor blockade . Although ETB receptor gene expression increases during late gestation, th e balance of ET receptor activity favors vasoconstriction under basal condi tions. We speculate that changes in ET receptor activity play important rol es in regulation of pulmonary vascular tone in the ovine fetus.