MicroRNA-210-mediated mtROS confer hypoxia-induced suppression of STOCs in ovine uterine arteries

Abstract

Background and purpose: Hypoxia during pregnancy is associated with increased uterine vascular resistance and elevated blood pressure both in women and female sheep. A previous study demonstrated a causal role of microRNA-210 (miR-210) in gestational hypoxia-induced suppression of Ca²⁺ sparks/spontaneous transient outward currents (STOCs) in ovine uterine arteries, but the underlying mechanisms remain undetermined. We tested the hypothesis that miR-210 perturbs mitochondrial metabolism and increases mitochondrial reactive oxygen species (mtROS) that confer hypoxia-induced suppression of STOCs in uterine arteries.

Experimental approach: Resistance-sized uterine arteries were isolated from near-term pregnant sheep and were treated ex vivo in normoxia and hypoxia (10.5% O₂ ) for 48 h.

Key results: Hypoxia increased mtROS and suppressed mitochondrial respiration in uterine arteries, which were also produced by miR-210 mimic to normoxic arteries and blocked by antagomir miR-210-LNA in hypoxic arteries. Hypoxia or miR-210 mimic inhibited Ca²⁺ sparks/STOCs and increased uterine arterial myogenic tone, which were inhibited by the mitochondria-targeted antioxidant MitoQ. Hypoxia and miR-210 down-regulated iron-sulfur cluster scaffold protein (ISCU) in uterine arteries and knockdown of ISCU via siRNAs suppressed mitochondrial respiration, increased mtROS, and inhibited STOCs. In addition, blockade of mitochondrial electron transport chain with antimycin and rotenone inhibited large-conductance Ca²⁺ -activated K⁺ channels, decreased STOCs and increased uterine arterial myogenic tone.

Conclusion and implications: This study demonstrates a novel mechanistic role for the miR-210-ISCU-mtROS axis in inhibiting Ca²⁺ sparks/STOCs in the maladaptation of uterine arteries and provides new insights into the understanding of mitochondrial perturbations in the pathogenesis of pregnancy complications resulted from hypoxia.

Keywords: Ca2+ sparks; STOCs; hypoxia; mitochondria; pre-eclampsia; pregnancy; reactive oxygen species.