title: Effects of chronic estrogen-receptor blockade on ovine perinatal pulmonary circulation.
abstract: Prolonged infusions of 17beta-estradiol reduce fetal pulmonary vascular resistance (PVR), but the effects of endogenous estrogens in the fetal pulmonary circulation are unknown. To test the hypothesis that endogenous estrogen promotes pulmonary vasodilation at birth, we studied the hemodynamic effects of prolonged estrogen-receptor blockade during late gestation and at birth in fetal lambs. We treated chronically prepared fetal lambs with ICI-182,780 (ICI, a specific estrogen-receptor blocker, n = 5) or 1% DMSO (CTRL, n = 5) for 7 days and then measured pulmonary hemodynamic responses to ventilation with low- and high-fraction inspired oxygen (FI(O(2))). 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 FI(O(2)) [change in PVR -30 +/- 6% (CTRL) vs. +10 +/- 13%, (ICI), P < 0.05] without reducing the vasodilator response to ventilation with high FI(O(2)) [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 revealed that PGIS is predominantly expressed in the airway epithelium of late gestation fetal lambs. We conclude that prolonged estrogen-receptor blockade inhibits the pulmonary vasodilator response at birth and that this effect may be mediated by downregulation of PGIS. We speculate that estrogen exposure during late gestation prepares the pulmonary circulation for postnatal adaptation.
authors.affiliation: The Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado 80262, USA. parker.thomas@tchden.org
authors.forename: T A
authors.initials: TA
authors.lastname: Parker
authors.forename: S
authors.initials: S
authors.lastname: Afshar
authors.forename: J P
authors.initials: JP
authors.lastname: Kinsella
authors.forename: T R
authors.initials: TR
authors.lastname: Grover
authors.forename: S
authors.initials: S
authors.lastname: Gebb
authors.forename: M
authors.initials: M
authors.lastname: Geraci
authors.forename: P W
authors.initials: PW
authors.lastname: Shaul
authors.forename: C M
authors.initials: CM
authors.lastname: Cryer
authors.forename: S H
authors.initials: SH
authors.lastname: Abman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004334:Drug Administration Schedule; D004958:Estradiol / Q000008:administration & dosage* / Q000031:analogs & derivatives; D004965:Estrogen Antagonists / Q000008:administration & dosage*; D005260:Female; D005333:Fetus / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D000077267:Fulvestrant; D006439:Hemodynamics / Q000187:drug effects; D007261:Infusions, Intra-Arterial / Q000379:methods; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000196:embryology / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009928:Organ Specificity; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011651:Pulmonary Artery / Q000196:embryology / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D012123:Pulmonary Ventilation / Q000187:drug effects; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors*; D012756:Sheep; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D004965:Estrogen Antagonists; D007527:Isoenzymes; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D009569:Nitric Oxide; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase