Abstract Chronic hypoxia during pregnancy increases uterine artery L‐type Ca V 1.2 channel currents and uterine vascular resistance in pregnant ewes. In the present study, we tested the hypothesis that microRNA‐210‐mediated mitochondrial oxidative stress contributes to gestational hypoxia‐induced Ca V 1.2 channel hyperactivity of uterine arteries. In a pregnant sheep model acclimatized to high‐altitude hypoxia, we found that knockdown of endogenous microRNA‐210 with microRNA‐210 locked nucleic acid diminished hypoxia‐induced Ca V 1.2 hyperactivity in uterine arteries. Accordingly, microRNA‐210 mimic recapitulated the effect of hypoxia to increase Ca V 1.2 activity and window currents of uterine arteries from normoxic pregnant ewes. Mechanistically, we revealed that microRNA‐210 mediated gestational hypoxia‐induced suppression of mitochondrial respiration and increase of mitochondrial reactive oxygen species in uterine arteries. We provided evidence that MitoQ, a mitochondria‐targeted antioxidant, blocked both gestational hypoxia‐ and microRNA‐210‐mediated Ca V 1.2 hyperactivity in uterine arteries from pregnant ewes. In addition, microRNA‐210 significantly increased phenylephrine‐induced vasoconstriction of uterine arteries of pregnant ewes, an effect that was inhibited by MitoQ. Thus, our study provides new evidence of a mechanistic link of microRNA‐210‐mediated mitochondrial oxidative stress in gestational hypoxia‐induced L‐type Ca V 1.2 channel hyperactivity of uterine arteries in an animal model of pregnant sheep and reveals potential targets for therapeutic interventions of pregnancy complications associated with chronic hypoxia. image Key points Knockdown of endogenous microRNA‐210 with microRNA‐210 locked nucleic acid diminished hypoxia‐induced Ca V 1.2 hyperactivity in uterine arteries. MicroRNA‐210 mimic recapitulated the effect of hypoxia to increase Ca V 1.2 activity and window currents of uterine arteries from normoxic pregnant ewes. MicroRNA‐210 mediated gestational hypoxia‐induced suppression of mitochondrial respiration and increase of mitochondrial reactive oxygen species in uterine arteries. MitoQ, a mitochondria‐targeted antioxidant, blocked both gestational hypoxia‐ and microRNA‐210‐mediated Ca V 1.2 hyperactivity in uterine arteries from pregnant ewes. MicroRNA‐210 significantly increased phenylephrine‐induced vasoconstriction of uterine arteries of pregnant ewes, an effect that was inhibited by MitoQ.
Hu et al. (Sat,) studied this question.