title: Maternal high-altitude hypoxia and suppression of ryanodine receptor-mediated Ca2+ sparks in fetal sheep pulmonary arterial myocytes.
abstract: Ca(2+) sparks are fundamental Ca(2+) signaling events arising from ryanodine receptor (RyR) activation, events that relate to contractile and dilatory events in the pulmonary vasculature. Recent studies demonstrate that long-term hypoxia (LTH) can affect pulmonary arterial reactivity in fetal, newborn, and adult animals. Because RyRs are important to pulmonary vascular reactivity and reactivity changes with ontogeny and LTH we tested the hypothesis that RyR-generated Ca(2+) signals are more active before birth and that LTH suppresses these responses. We examined these hypotheses by performing confocal imaging of myocytes in living arteries and by performing wire myography studies. Pulmonary arteries (PA) were isolated from fetal, newborn, or adult sheep that lived at low altitude or from those that were acclimatized to 3,801 m for > 100 days. Confocal imaging demonstrated preservation of the distance between the sarcoplasmic reticulum, nucleus, and plasma membrane in PA myocytes. Maturation increased global Ca(2+) waves and Ca(2+) spark activity, with sparks becoming larger, wider, and slower. LTH preferentially depressed Ca(2+) spark activity in immature pulmonary arterial myocytes, and these sparks were smaller, wider, and slower. LTH also suppressed caffeine-elicited contraction in fetal PA but augmented contraction in the newborn and adult. The influence of both ontogeny and LTH on RyR-dependent cell excitability shed new light on the therapeutic potential of these channels for the treatment of pulmonary vascular disease in newborns as well as adults.
authors.affiliation: Center for Perinatal Biology, Loma Linda University, California 92350, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Hadley
authors.forename: Quintin
authors.initials: Q
authors.lastname: Blood
authors.forename: Monica
authors.initials: M
authors.lastname: Rubalcava
authors.forename: Edith
authors.initials: E
authors.lastname: Waskel
authors.forename: Britney
authors.initials: B
authors.lastname: Lumbard
authors.forename: Petersen
authors.initials: P
authors.lastname: Le
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Longo
authors.forename: John N
authors.initials: JN
authors.lastname: Buchholz
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wilson
mesh_terms: D000064:Acclimatization; D000704:Analysis of Variance; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D020013:Calcium Signaling; D015687:Cell Hypoxia; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000502:physiology; D011188:Potassium / Q000378:metabolism / Q000502:physiology; D011247:Pregnancy; D011651:Pulmonary Artery / Q000166:cytology* / Q000503:physiopathology; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism* / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012756:Sheep; D018709:Statistics, Nonparametric
chemical_list: D002120:Calcium Channel Agonists; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D002110:Caffeine; D011188:Potassium