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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Physiol. | doi: 10.3389/fphys.2019.01032

Long-term high altitude hypoxia and alpha adrenoceptor-dependent pulmonary arterial contractions in fetal and adult sheep.

 Dafne Moretta1, Demosthenes G. Papamatheakis2,  Daniel Morris1,  Paresh C. Giri3, Quintin Blood1, Samuel Murray1, Marian Ramzy1,  Monica Romero4, Srilakshmi Vemulakonda1,  Sidney Lauw1,  Lubo Zhang1 and  Sean M. Wilson5*
  • 1School of Medicine, Loma Linda University, United States
  • 2University of California, San Diego, United States
  • 3Pulmonary and Critical Care, School of Medicine, Loma Linda University, United States
  • 4Advanced Imaging and Microscopy, School of Medicine, Loma Linda University, United States
  • 5Lawrence D Longo Center for Perinatal Biology, School of Medicine, Loma Linda University, United States

Autonomic innervation of the pulmonary vasculature triggers vasomotor contractility predominately through activation of alpha-adrenergic receptors (α-AR) in the fetal circulation. Long term hypoxia (LTH) modulates pulmonary vasoconstriction potentially through up-regulation of α1-AR in the vasculature. Our study aimed to elucidate the role of α-AR in phenylephrine (PE)-induced pulmonary vascular contractility, comparing the effects of LTH in the fetal and adult periods on α-AR subtypes and PE-mediated Ca2+ responses and contractions. To address this, we performed wire myography, Ca2+ imaging and mRNA analysis of pulmonary arteries from ewes and fetuses exposed to LTH or normoxia. Postnatal maturation depressed PE-mediated contractile responses. α2-AR activation contracted fetal vessels; however, this was suppressed by LTH. α1A- and α1B-AR subtypes contributed to arterial contractions in all groups. The α1D-AR was also important to contractility in fetal normoxic vessels and LTH mitigated its function. Postnatal maturity increased the number of myocytes with PE triggered Ca2+ responses while LTH decreased the percentage of fetal myocytes reacting to PE. The difference between myocyte Ca2+ responsiveness and vessel contractility suggests that fetal arteries are sensitized to changes in Ca2+. The results illustrate that α-adrenergic signaling and vascular function change during development and that LTH modifies adrenergic signaling. These adaptations may represent components in the etiology of pulmonary vascular disease and foretell the therapeutic potential of adrenergic receptor antagonists in the treatment of pulmonary hypertension.

Keywords: Sheep, Fetus, adrenergic receptor, Contraction, Calcium, hypoxia, Pulmonary Artery

Received: 01 May 2019; Accepted: 26 Jul 2019.

Edited by:

Francisco C. Villafuerte, Universidad Peruana Cayetano Heredia, Peru

Reviewed by:

Satoshi Iwase, Aichi Medical University, Japan
Patricia Siques, Arturo Prat University, Chile  

Copyright: © 2019 Moretta, Papamatheakis, Morris, Giri, Blood, Murray, Ramzy, Romero, Vemulakonda, Lauw, Zhang and Wilson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Sean M. Wilson, School of Medicine, Loma Linda University, Lawrence D Longo Center for Perinatal Biology, Loma Linda, 92350, California, United States, seanwilson@llu.edu