Gestational high altitude long term hypoxia and impact of oxidative stress on ryanodine receptor activity in pulmonary arterial myocytes of fetal sheep

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High altitude exposure reduces the oxygen tension in ambient air. The resultant hypoxia induces oxidative stress and causes vasoconstriction of the blood vessels within the pulmonary vasculature that can result in pulmonary hypertension. Previously we found that high altitude gestation deregulated Ca2+ spark activity in fetal pulmonary arteries, which is due to local ryanodine receptor (RyR) activation. These Ca2+ sparks are thought to be coupled to vasodilatory pathways and are important to vasodilation at birth, Furthermore, RyR activity is affected by the redox-status of the protein. Thus, the elevated oxidative stress in pulmonary arteries due to high altitude exposure may underlie the dysregulation in Ca2+ spark activity. We hypothesized that high altitude mediated long term hypoxia alters the impact of oxidative stress on Ca2+ spark activity. This hypothesis was examined in pulmonary arterial (PA) myocytes from low altitude (335m) and high altitude acclimatized fetal sheep (~3,800m for <100 days). Intracellular Ca2+ sparks were recorded within the myocytes of smooth muscle cells using line-scan confocal imaging of the Ca2+ indicator Fluo-4. Oxidative stress was elevated with acute exposure to tert-butyl H2O2 (TbH2O2) or reduced with the antioxidant N-Acetyl-Cysteine (NAC). Ca2+ spark activity and spatial-temporal properties were analyzed with automated custom designed software (SparkLab). Increased oxidative stress with TbH2O2 failed to influence Ca2+ spark activity independent of altitude. Interestingly, NAC preferentially reduced Ca2+ spark activity in myocytes of normoxic pulmonary arteries. These data suggest that RyR activity and resultant Ca2+ sparks in high altitude fetal sheep are resistant to acute changes in cellular redox status. NIH R01HL155295 and R01HL149608, NSF Grant MRI-DBI 0923559 and the Loma Linda University School of Medicine This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.