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Pregnancy Enhances Calcium Spark Activity Independent of Altitude in Ovine Uterine Arterial Myocytes

During pregnancy, uterine artery blood flow increases in order to accommodate the growing fetus. However, the molecular mechanisms by which this change in uterine blood flow occurs remains to be elucidated. The BKCa channel, which is activated in response to ryanodine receptor (RyR) generated increases in intracellular Ca2+ known as Ca2+ sparks, helps regulate uterine artery blood flow. BKCa channel activation leads to vascular smooth muscle relaxation, thus decreasing uterine artery vascular tone and increasing uterine blood flow during pregnancy. Further to this, long term hypoxia due to high altitude exposure diminishes pregnancy – related increases in uterine blood flow. Based on these relationships we hypothesized that both pregnancy and membrane depolarization would increase Ca2+ spark activity, whereas ryanodine and long term hypoxia would inhibit Ca2+ spark activity. Uterine arteries were isolated from near‐term pregnant (n=6) and non‐pregnant sheep (n=6) in normoxia, as well as near‐term pregnant (n=6) and non‐pregnant sheep (n=6) exposed to hypoxic conditions at White Mountain (elevation 3,801 m) for 100 plus days. Isolated uterine arteries were subjected to three distinct ex vivo treatments: (1) control (saline), (2) 30mM potassium (30K), which causes membrane depolarization, and (3) 30K with ryanodine (10 μM), an RyR antagonist. Indeed, Ca2+ spark activity was increased in pregnant uterine arteries as compared to non‐pregnant uterine arteries, whereas hypoxia reduced spark frequency in all the aforementioned groups. Treatment with 30K increased Ca2+ spark activity in all groups. In comparison, 30K + ryanodine treatment decreased Ca2+ spark activity. Pregnancy increased the full width of sparks. However, pregnancy or hypoxia caused only minor changes in the amplitude and temporal aspects of sparks. These findings support the claim that membrane depolarization, due to 30K treatment, causes an increase in Ca2+ spark activity whereas ryanodine inhibits release of Ca2+ from the sarcoplasmic reticulum and thus decreases Ca2+ sparks. Taken together, these findings support the notion that the ryanodine receptors and BKCa channels work in conjunction with each other. This study provides further insight into the mechanisms that regulate uterine artery vascular tone and blood flow, and thus may prove useful in designing treatments for pregnancy complications that arise from increased uterine vascular tone, such as intrauterine growth restriction.