LAUSR

Objectives: We determined the effect of chronic hypoxia during gestation on uterine vascular resistance and maternal blood pressure. Methods: The study was performed in sheep acclimatized to high altitude. Results: We demonstrated that high altitude hypoxia abolished the pregnancy-induced decrease in blood pressure and significantly increased systolic and mean arterial blood pressure in pregnant sheep. Gestational hypoxia resulted in 45% increase in uterine vascular resistance in pregnant animals. We further demonstrated that the large conductance Ca2+-activated K+ (BKCa) channel played an essential role in uterine hemodynamic adaptation to pregnancy. Gestational hypoxia suppressed pregnancy and steroid hormone-induced upregulation of BKCa channel expression and function in uterine arteries. High altitude hypoxia significantly increased microRNA-210 levels in uterine arteries. Blockade of endogenous microRNA-210 with microR210-LNA relieved hypoxia-mediated suppression of BKCa channel expression, channel activity and BKCa channel-induced relaxations. In addition, the microR210-LNA treatment restored the ability of steroid hormones in enhancing BKCa channel expression and activity and augmented BKCa channel-mediated relaxations of uterine arteries from nonpregnant sheep. Accordingly, microR210-LNA significantly decreased pressure-dependent myogenic tone in uterine arteries from pregnant sheep and enabled steroid hormones to reduce uterine arterial myogenic tone. Conclusion: Together, our data revealed that microR-210 played a critical role in hypoxia-induced BKCa channel dysfunction in uterine arteries during gestation. More importantly, we demonstrated that gestational hypoxia-induced impairment of BKCa channel expression and function could be amended by the antimiR oligonucleotide microR210-LNA.