Long-term high altitude hypoxia during gestation suppresses large conductance Ca2+ -activated K+ channel function in uterine arteries: a causal role for microRNA-210.

KEY POINTS: Gestational hypoxia represses ten-eleven translocation methylcytosine dioxygenase 1 (TET1) expression in uterine arteries, which is recovered by inhibiting endogenous miR-210. Inhibition of miR-210 rescues BKCa channel expression and current in uterine arteries of pregnant animals acclimatized to high altitude hypoxia in a TET-dependent manner. miR-210 blockade restores BKCa channel-mediated relaxations and attenuates pressure-dependent myogenic tone in uterine arteries of pregnant animals acclimatized to high altitude. ABSTRACT: Gestational hypoxia at high altitude has profound adverse effects on the uteroplacental circulation, and is associated with increased incidence of preeclampsia and fetal intrauterine growth restriction. Previous studies demonstrated that suppression of large-conductance Ca2+ -activated K+ (BKCa ) channel function played a critical role in the maladaptation of uteroplacental circulation caused by gestational hypoxia. Yet, the mechanisms underlying gestational hypoxia-induced BKCa channel repression remain undetermined. The present study investigated a causal role of microRNA-210 (miR-210) in hypoxia-mediated repression of BKCa channel expression and function in uterine arteries using a sheep model. The results revealed that gestational hypoxia significantly decreased ten-eleven translocation methylcytosine dioxygenase 1 (TET1) expression in uterine arteries, which was recovered by inhibiting endogenous miR-210 with miR-210 locked nucleic acid (miR-210-LNA). Of importance, miR-210-LNA restored BKCa channel β1 subunit expression in uterine arteries, which was blocked by a competitive TET inhibitor, fumarate, thus functionally linking miR-210 to the TET1-BKCa channel cascade. In addition, miR-210-LNA reversed hypoxia-mediated suppression of BKCa channel function and rescued the effect of steroid hormones in upregulating BKCa channel expression and function in uterine arteries, which were also ablated by fumarate. Collectively, the present study demonstrates a causative effect of miR-210 in the downregulation of TET1 and subsequent repression of BKCa channel expression and function, providing a novel mechanistic insight into the regulation of BKCa channel function and the molecular basis underlying the maladaptation of uterine vascular function in gestational hypoxia.