Chronic And Acute Hypoxia Markedly Alter Ca2+Signaling In Adult And Fetal Pulmonary Arterial Myocytes

Ca2+ signaling is well regarded as being vital to hypoxic induced pulmonary arterial (PA) vasoconstriction and chronic high altitude living can exacerbate this process. To test the hypothesis that chronic hypoxia will increase Ca2+ wave activity due to acute hypoxia in pulmonary arterial myocytes (PAM) of both fetal and adult sheep and better understand the Ca2+ signals, we exposed pregnant and non‐pregnant ewes to 3800m for >110 days to induce chronic hypoxia. We then performed confocal imaging of PAM in Fluo‐4 loaded intact arteries using an en face preparation. Images were recorded in an atmospheric chamber at ~37°C adjusted to either normoxic conditions, at ~300m, or acute hypoxic conditions, simulated by exposing PAs to ~4% O2 for 30 min. Ca2+ signal characteristics in regions of interest (ROIs) were examined with automated analysis procedures. Chronic hypoxia increased Ca2+ wave size in adults, rate of cytosolic Ca2+ removal in fetuses, and ROI recruitment in adults, albeit most ROIs occured in the same cell. Acute hypoxia decreased Ca2+ wave size in chronically hypoxic adults and decreased ROI recruitment in normoxic but not chronically hypoxic adults. It also reduced Ca2+ wave size in normoxic fetuses and obliterated Ca2+ signaling in chronically hypoxic fetuses. Maturation increased Ca2+ wave size as well as recruited more ROIs across the artery wall. These results indicate that chronic hypoxia modifies the influence of acute hypoxia on Ca2+ signaling in fetal and adult PAM in marked ways that may be important to pulmonary vascular dysfunction in those who live and are born at high altitude.Support or Funding InformationSupport from NIH, NSF, and the Walter E. Macpherson Society