AMP-activated protein kinase activator AICAR attenuates hypoxia-induced murine fetal growth restriction in part by improving uterine artery blood flow.
AMP-activated protein kinase activator AICAR attenuates hypoxia-induced murine fetal growth restriction in part by improving uterine artery blood flow.
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DOI：
10.1113/jp279341
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Moore LG
中科院分区：
文献类型：
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作者：
Lane SL;Houck JA;Doyle AS;Bales ES;Lorca RA;Julian CG;Moore LG
子宫胎盘缺氧与妊娠障碍有关，如宫内生长受限和先兆子痫，其特征是子宫胎盘缺血和/或胎儿缺氧。amp活化蛋白激酶（AMPK）的激活导致血管舒张，因此是恢复妊娠疾病子宫胎盘灌注的潜在治疗策略。在这项研究中，C57Bl/6小鼠从妊娠第13.5天开始皮下注射含有载药、AMPK激活剂AICAR （200 mg/kg/天）或AMPK抑制剂化合物C （20 mg/kg/天）的微丸，并从妊娠第14.5天开始暴露于缺氧环境中，导致宫内生长受限。AICAR激活AMPK部分阻止了缺氧诱导的胎儿生长受限（p<0.01），部分原因是子宫动脉血流量增加（p<0.0001）。缺氧小鼠经AICAR后，总心输出量经子宫动脉的比例增加（p<0.001），提示AICAR对子宫循环的血管扩张作用具有选择性。此外，复方C对AMPK的药理学抑制降低了正常妊娠小鼠的子宫动脉直径，增加了子宫动脉的收缩力，这证明了AMPK的生理水平激活对于健康妊娠的血管扩张是必要的。双向方差分析表明，与对照组相比，缺氧降低了子宫动脉和胎盘中AMPK的激活，而AICAR增加了这些组织中AMPK的激活。这些发现为进一步研究AMPK药理激活治疗胎儿生长受限的效用提供了支持。
Uteroplacental hypoxia is associated with pregnancy disorders such as intrauterine growth restriction and preeclampsia, which are characterized by uteroplacental ischemia and/or fetal hypoxia. Activation of AMP-activated protein kinase (AMPK) results in vasodilation and is therefore a potential therapeutic strategy for restoring uteroplacental perfusion in pregnancy disorders. In this study, C57Bl/6 mice were treated with subcutaneous pellets containing vehicle, the AMPK activator AICAR (200 mg/kg/day), or the AMPK inhibitor Compound C (20 mg/kg/day) beginning on gestational day 13.5, and were exposed to hypoxia starting on gestational day 14.5 that induced intrauterine growth restriction. Pharmacologic AMPK activation by AICAR partially prevented hypoxia-induced fetal growth restriction (p<0.01), due in part to increased uterine artery blood flow (p<0.0001). The proportion of total cardiac output flowing through the uterine artery was increased with AICAR in hypoxic mice (p<0.001), suggesting that the vasodilator effect of AICAR was selective for the uterine circulation. Further, pharmacologic inhibition of AMPK with Compound C reduced uterine artery diameter and increased uterine artery contractility in normoxic mice, providing evidence that physiologic levels of AMPK activation are necessary for vasodilation in healthy pregnancy. Two-way ANOVA analyses indicated that hypoxia reduced AMPK activation in the uterine artery and placenta, and AICAR increased AMPK activation in these tissues compared to vehicle. These findings provide support for further investigation into the utility of pharmacologic AMPK activation for treatment of fetal growth restriction.