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Long-Term Maternal Hypoxia

The Role of Extracellular Ca2+ Entry During Serotonin-Mediated Contractility in Fetal Ovine Pulmonary Arteries

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Abstract

Antenatal maternal long-term hypoxia (LTH) can alter serotonin (5-HT) and calcium (Ca2+) 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 Ca2+ influx through L-type Ca2+ channels (CaL), nonselective cation channels (NSCCs), and reverse-mode sodium–calcium exchanger (NCX) in the near-term fetus. We performed wire myography and confocal-Ca2+ 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-HT2A antagonist, shifted 5-HT potency irrespective of LTH, while GR-55562 (1 µmol/L), a 5-HT1B/D inhibitor, antagonized 5-HT-induced contraction in normoxic fetuses only. Various inhibitors for CaL, NSCC, and reverse-mode NCX were used in contraction studies. Contraction was reliant on extracellular Ca2+ regardless of maternal hypoxia, NSCC was more important to contraction than CaL, 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 Ca2+ responses observed by imaging studies. Overall, LTH reduced 5HT1B/D function and increased NSCC-related Ca2+-dependent contraction in ovine fetuses, which may compromise pulmonary vascular function in the newborn.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology and Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA, USA

    Ravi Goyal MBBS, PhD, Kurt Vrancken MS, Arlin B. Blood PhD, William J. Pearce PhD, Lawrence D. Longo MD & Sean M. Wilson PhD

  2. Department of Medicine, Division of Pulmonary and Critical Care, Loma Linda University Medical Center, Loma Linda, CA, USA

    Demosthenes G. Papamatheakis MD & Sean M. Wilson PhD

  3. Department of Pharmacology, School of Pharmacy and Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS, USA

    Matthew Loftin Pharm D, Antoinette S. Dawson BS & Noah J. Osman BS

  4. Department of Pediatrics, Division of Neonatology, School of Medicine, Loma Linda University, Loma Linda, CA, USA

    Kurt Vrancken MS & Arlin B. Blood PhD

  5. Light Microscopy Core, University of Mississippi, University, MS, USA

    Antoinette S. Dawson BS & Noah J. Osman BS

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  1. Ravi Goyal MBBS, PhD
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Goyal, R., Papamatheakis, D.G., Loftin, M. et al. Long-Term Maternal Hypoxia. Reprod. Sci. 18, 948–962 (2011). https://doi.org/10.1177/1933719111401660

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