Effects of chronic estrogen-receptor blockade on ovine perinatal pulmonarycirculation

Prolonged infusions of 17 beta -estradiol reduce fetal pulmonary vascular r esistance (PVR), but the effects of endogenous estrogens in the fetal pulmo nary circulation are unknown. To test the hypothesis that endogenous estrog en promotes pulmonary vasodilation at birth, we studied the hemodynamic eff ects of prolonged estrogen-receptor blockade during late gestation and at b irth in fetal lambs. We treated chronically prepared fetal lambs with ICI-1 82,780 (ICI, a specific estrogen-receptor blocker, n = 5) or 1% DMSO (CTRL, n = 5) for 7 days and then measured pulmonary hemodynamic responses to ven tilation with low- and high-fraction inspired oxygen (FIO2). Treatment with ICI did not change basal fetal PVR or arterial blood gas tensions. However , treatment with ICI abolished the vasodilator response to ventilation with low FIO2 [change in PVR -30 +/- 6% (CTRL) vs. +10 +/- 13%, (ICI), P < 0.05 ] without reducing the vasodilator response to ventilation with high FIO2 [ change in PVR, -73 +/- 3% (CTRL) vs. -77 +/- 4%, (ICI); P = not significant ]. ICI treatment reduced prostacyclin synthase (PGIS) expression by 33% (P < 0.05) without altering expression of endothelial nitric oxide synthase or cyclooxygenase-1 and -2. In situ hybridization and immunohistochemistry re vealed that PGIS is predominantly expressed in the airway epithelium of lat e gestation fetal lambs. We conclude that prolonged estrogen-receptor block ade inhibits the pulmonary vasodilator response at birth and that this effe ct may be mediated by downregulation of PGIS. We speculate that estrogen ex posure during late gestation prepares the pulmonary circulation for postnat al adaptation.