Expression and Function of Ca2+-Activated K+ Channels in Uterine Arteries
Chronic hypoxia during pregnancy is one of the most common insults to the maternal cardiovascular system and fetal development, and is associated with increased uterine vascular tone and heightened risk of preeclampsia and fetal intrauterine growth restriction (IUGR). The present study tested the hypothesis that calcium-activated potassium (KCa) channels play an essential role in uterine vascular adaptation to pregnancy, which is inhibited by chronic hypoxia during gestation. Uterine arteries (UAs) were isolated from nonpregnant ewes (NPUAs) and near-term pregnant ewes (PUAs) that had been maintained at sea level (~300 m) or exposed to high altitude (3,801 m) for 110 days. In normoxic animals, both BKCa and SKCa channels were expressed in uterine arterial smooth muscle cells and endothelial cells. Pregnancy selectively enhanced the protein abundances and mRNA levels of BKCa subunit 1 and SKCa subtype 2 and 3 in uterine arteries, resulting in enhanced both BKCa and SKCa channels activities and their-mediated relaxations, and decreased uterine vascular tone in PUAs as compared with those in NPUAs. Chronic treatment of NPUA with 17β-estradiol (E2β) and progesterone significantly increased BKCa and SKCa channel exspression and enhanced both BKCa activator NS1619- and SKCa activator NS309-induced relaxations of NPUAs. Chronic hypoxia during gestation significantly attenuated both NS1619- and NS309-induced relaxations of UAs, which was associated with decreases in BKCa and SKCa channel expression and their activities. Chronic hypoxia enhanced the inhibitory role of oxidative stress and PKC on KCa channel activities and their-mediated uterine arterial relaxation. In addition, chronic hypoxia ettenuated the effect of 17β-estradiol and progesterone in KCa-mediated relaxations in NPUAs. In conclusion, our results suggest an important role of KCa channels in the regulation of basal uterine vascular tone. Pregnancy-mediated decrease in uterine vascular tone is associated with an enhanced KCa channel expression and their activities, which is regulated by steroid hormones. Chronic hypoxia during gestation attenuates the effect of steroid hormone on KCa channels, resulting in decreased KCa channel-mediated relaxations and increased uterine vascular tone.
Biochemistry, Biophysics, and Structural Biology, Medical Biochemistry, Medicine and Health Sciences, Uterine Artery; Anoxia; Vasodilation; Potassium Channels - Calcium-Activated; Small-Conductance Calcium-Activated Potassium Channel Alpha Subunits; Reactive Oxygen Species; Estradiol; Progesterone; Vascular Resistance; Pregnancy Complications; Fetal Hypoxia; Fetal Development, Fetal Intrauterine Growth Restriction; Uterine Vascular Adaptation; Basal Uterine Vascular Tone;
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