title: Long-term maternal hypoxia: the role of extracellular Ca2+ entry during serotonin-mediated contractility in fetal ovine pulmonary arteries.
abstract: Antenatal maternal long-term hypoxia (LTH) can alter serotonin (5-HT) and calcium (Ca(2+)) signaling in fetal pulmonary arteries (PAs) and is associated with persistent pulmonary hypertension of the newborn (PPHN). In humans, the antenatal maternal hypoxia can be secondary to smoking, anemia, and chronic obstructive pulmonary disorders. However, the mechanisms of antenatal maternal hypoxia-related PPHN are unresolved. Because both LTH and 5-HT are associated with PPHN, we tested the hypothesis that antenatal maternal LTH can increase 5-HT-mediated PA contraction and associated extracellular Ca(2+) influx through L-type Ca(2+) channels (Ca(L)), nonselective cation channels (NSCCs), and reverse-mode sodium-calcium exchanger (NCX) in the near-term fetus. We performed wire myography and confocal-Ca(2+) imaging approaches on fetal lamb PA (∼ 140 days of gestation) from normoxic ewes or those acclimatized to high-altitude LTH (3801 m) for ∼110 days. Long-term hypoxia reduced the potency but not the efficacy of 5-HT-induced PA contraction. Ketanserin (100 nmol/L), a 5-HT(2A) antagonist, shifted 5-HT potency irrespective of LTH, while GR-55562 (1 µmol/L), a 5-HT(1B/D) inhibitor, antagonized 5-HT-induced contraction in normoxic fetuses only. Various inhibitors for Ca(L), NSCC, and reverse-mode NCX were used in contraction studies. Contraction was reliant on extracellular Ca(2+) regardless of maternal hypoxia, NSCC was more important to contraction than Ca(L), and reverse-mode NCX had little or no role in contraction. Long-term hypoxia also attenuated the effects of 2-APB and flufenamic acid and reduced Ca(2+) responses observed by imaging studies. Overall, LTH reduced 5HT(1B/D) function and increased NSCC-related Ca(2+)-dependent contraction in ovine fetuses, which may compromise pulmonary vascular function in the newborn.
authors.affiliation: Department of Physiology and Pharmacology and Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Goyal
authors.forename: Demosthenes G
authors.initials: DG
authors.lastname: Papamatheakis
authors.forename: Matthew
authors.initials: M
authors.lastname: Loftin
authors.forename: Kurt
authors.initials: K
authors.lastname: Vrancken
authors.forename: Antoinette S
authors.initials: AS
authors.lastname: Dawson
authors.forename: Noah J
authors.initials: NJ
authors.lastname: Osman
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Blood
authors.forename: William J
authors.initials: WJ
authors.lastname: Pearce
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Longo
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D005260:Female; D005333:Fetus; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D011247:Pregnancy; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D012756:Sheep / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: D012702:Serotonin Antagonists; D012701:Serotonin; D007650:Ketanserin; D002118:Calcium