MicroRNA-210 Mediates Hypoxia-Induced Repression of Spontaneous Transient Outward Currents in Sheep Uterine Arteries During Gestation

Abstract

Hypoxia during pregnancy is a major contributor to the pathogenesis of preeclampsia and intrauterine growth restriction. Our recent studies revealed that pregnancy-induced uterine vascular adaptation depended on the enhanced Ca 2+ spark/spontaneous transient outward current (STOC) coupling and hypoxia during gestation diminished this adaption. In the present study, we test the hypothesis of a mechanistic link of microRNA-210 (miR-210) in hypoxia-impaired Ca 2+ spark/STOC coupling in uterine arteries. Pregnant ewes acclimatized to high-altitude (3801 m) hypoxia for ≈110 days significantly increased circulation levels of miR-210 in both the ewe and her fetus. Treatment of uterine arteries from high-altitude animals with the antagomir miR-210-LNA recovered hypoxia-repressed STOCs in pregnant ewes and restored the hormonal regulation of STOCs in nonpregnant animals. In uterine arteries from low-altitude control animals, miR-210 mimic suppressed STOCs in pregnant ewes and inhibited the hormonal regulation of STOCs in nonpregnant animals. Mechanistically, miR-210 directly targeted and downregulated type 2 ryanodine receptor and large-conductance Ca 2+ -activated K + channel β1 subunit, resulting in significant decreases in Ca 2+ sparks and STOCs in uterine arteries. In addition, miR-210 indirectly decreased STOCs by targeting ten-eleven translocation methylcytosine dioxygenase. Together, the present study revealed a mechanistic link of miR-210 in hypoxia-induced repression of Ca 2+ spark/STOC coupling in uterine arteries during gestation, providing novel insights into the understanding of pregnancy complications associated with hypoxia and the potential therapeutic targets.