MicroRNA-210 Mediates Hypoxia-Induced Repression of Spontaneous Transient Outward Currents in Sheep Uterine Arteries During Gestation.
MicroRNA-210 Mediates Hypoxia-Induced Repression of Spontaneous Transient Outward Currents in Sheep Uterine Arteries During Gestation.
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DOI：
10.1161/hypertensionaha.120.16831
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Zhang L
中科院分区：
文献类型：
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作者：
Hu XQ;Dasgupta C;Song R;Romero M;Wilson SM;Zhang L
妊娠期缺氧是先兆子痫和胎儿宫内生长受限的主要发病机制。我们最近的研究表明，妊娠诱导的子宫血管适应依赖于增强的Ca 2+火花/自发性瞬时外向电流（STOC）耦合和缺氧在妊娠期间削弱了这种适应。在本研究中，我们测试的一个机制链接的microRNA-210（miR-210）在缺氧受损的子宫动脉中的Ca 2+火花/STOC耦合的假设。妊娠母羊适应高海拔（3，801 m）缺氧约110天，显著增加了母羊及其胎儿中miR-210的循环水平。用Eschomir miR-210-LNA处理来自高海拔动物的子宫动脉恢复了妊娠母羊中缺氧抑制的STOC，并恢复了非妊娠动物中STOC的激素调节。在来自低海拔对照动物的子宫动脉中，miR-210模拟物抑制妊娠母羊中的STOC，并抑制非妊娠动物中STOC的激素调节。在机制上，miR-210直接靶向并下调2型ryanodine受体和大电导Ca 2+激活的K+通道β1亚基，导致子宫动脉中Ca 2+火花和STOCs显著减少。此外，miR-210通过靶向10 - 11易位甲基胞嘧啶双加氧酶间接降低STOC。总之，本研究揭示了miR-210在妊娠期间子宫动脉中缺氧诱导的Ca 2+火花/STOC偶联抑制中的机制联系，为理解与缺氧相关的妊娠并发症和潜在的治疗靶点提供了新的见解。目前的研究表明，miR-210升高是必要的，并足以通过下调RyR 2，BKCa β1亚基和TET 1来抑制子宫动脉适应妊娠缺氧的Ca 2+火花/STOC偶联。这项研究为理解妊娠缺氧引起的血管功能障碍的基本机制提供了新的见解，影响了母体心血管健康和发育可塑性。
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 Ca2+ 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 Ca2+ spark/STOC coupling in uterine arteries. Pregnant ewes acclimatized to high altitude (3,801 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 non-pregnant 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 non-pregnant animals. Mechanistically, miR-210 directly targeted and downregulated type 2 ryanodine receptor and large-conductance Ca2+-activated K+ channel β1 subunit, resulting in significant decreases in Ca2+ 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 Ca2+ 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. The present study demonstrates that elevated miR-210 is necessary and sufficient to inhibit Ca2+ spark/STOC coupling in uterine arterial adaptation to gestational hypoxia by downregulating RyR2, BKCa β1 subunit and TET1. The study provides new insights into the understanding of fundamental mechanisms underlying programming of vascular dysfunction caused by gestational hypoxia, impacting on maternal cardiovascular health and developmental plasticity.