Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA.
Br J Pharmacol. 2022 Oct;179(19):4640-4654. doi: 10.1111/bph.15914. Epub 2022 Jul 17.
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 Ca 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.
Resistance-sized uterine arteries were isolated from near-term pregnant sheep and were treated ex vivo in normoxia and hypoxia (10.5% O ) for 48 h.
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 Ca 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 Ca -activated K channels, decreased STOCs and increased uterine arterial myogenic tone.
This study demonstrates a novel mechanistic role for the miR-210-ISCU-mtROS axis in inhibiting Ca 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.
怀孕期间缺氧会导致子宫血管阻力增加，血压升高，无论是在女性还是雌性绵羊中都是如此。先前的研究表明，微小 RNA-210（miR-210）在妊娠缺氧诱导的绵羊子宫动脉钙火花/自发性瞬时外向电流（STOC）抑制中起因果作用，但潜在机制仍不清楚。我们假设 miR-210 会干扰线粒体代谢并增加线粒体活性氧（mtROS），从而导致子宫动脉中的缺氧诱导的 STOC 抑制，对此我们进行了验证。
从接近分娩的绵羊中分离出阻力大小的子宫动脉，并在常氧和缺氧（10.5% O ）中离体处理 48 小时。
缺氧增加了 mtROS 并抑制了子宫动脉中的线粒体呼吸，miR-210 模拟物也会导致常氧动脉出现这种情况，而在缺氧动脉中使用 miR-210 拮抗剂则可以阻断这种情况。缺氧或 miR-210 模拟物抑制了钙火花/STOCs 并增加了子宫动脉的肌源性张力，而这些作用均可被线粒体靶向抗氧化剂 MitoQ 抑制。缺氧和 miR-210 下调了子宫动脉中的铁硫簇支架蛋白（ISCU），通过 siRNA 敲低 ISCU 会抑制线粒体呼吸、增加 mtROS 并抑制 STOCs。此外，用抗霉素和鱼藤酮阻断线粒体电子传递链会抑制大电导钙激活的钾通道，减少 STOCs 并增加子宫动脉的肌源性张力。
本研究证明了 miR-210-ISCU-mtROS 轴在抑制子宫动脉适应不良中的钙火花/STOCs 中具有新的机制作用，并为理解缺氧引起的妊娠并发症发病机制中的线粒体扰动提供了新的见解。
