Integrated Physiology PhD Program, University of Colorado Graduate School, Aurora, CO, USA.
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO, USA.
J Physiol. 2020 Sep;598(18):4093-4105. doi: 10.1113/JP279341. Epub 2020 Jul 6.
Pregnancy at high altitude is associated with a greater incidence of fetal growth restriction due, in part, to lesser uterine artery blood flow. AMP-activated protein kinase (AMPK) activation vasodilates arteries and may increase uterine artery blood flow. In this study, pharmacological activation of AMPK by the drug AICAR improved fetal growth and elevated uterine artery blood flow. These results suggest that AMPK activation is a potential strategy for improving fetal growth and raising uterine artery blood flow in pregnancy, which may be important in pregnancy disorders characterized by uteroplacental ischaemia and/or fetal hypoxia.
Uteroplacental hypoxia is associated with pregnancy disorders such as intrauterine growth restriction and preeclampsia, which are characterized by uteroplacental ischaemia and/or fetal hypoxia. Activation of AMP-activated protein kinase (AMPK) results in vasodilatation 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. Pharmacological 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, pharmacological inhibition of AMPK with Compound C reduced uterine artery diameter and increased uterine artery contractility in normoxic mice, providing evidence that physiological levels of AMPK activation are necessary for vasodilatation 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 pharmacological AMPK activation for treatment of fetal growth restriction.
由于子宫动脉血流减少，高海拔地区妊娠与胎儿生长受限的发生率增加有关。 AMP 激活的蛋白激酶（AMPK）的激活可使动脉扩张，并可能增加子宫动脉血流。在这项研究中，药物 AICAR 对 AMPK 的药理学激活改善了胎儿生长并提高了子宫动脉血流。这些结果表明，AMPK 激活是改善妊娠中胎儿生长和提高子宫动脉血流的潜在策略，这在以胎盘缺血和/或胎儿缺氧为特征的妊娠疾病中可能很重要。
胎盘缺氧与宫内生长受限和子痫前期等妊娠疾病有关，这些疾病的特征是胎盘缺血和/或胎儿缺氧。 AMP 激活的蛋白激酶（AMPK）的激活可导致血管舒张，因此是恢复妊娠疾病中胎盘灌注的潜在治疗策略。在这项研究中，从妊娠第 13.5 天开始，将含有载体、AMPK 激活剂 AICAR（200mgkg-1d-1）或 AMPK 抑制剂 Compound C（20mgkg-1d-1）的皮下植入物给予 C57Bl/6 小鼠，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 对 AMPK 的药理学激活部分预防了缺氧引起的胎儿生长受限（P <0.01），部分原因是子宫动脉血流增加（P <0.0001）。在缺氧小鼠中，AICAR 增加了总心输出量通过子宫动脉的比例（P <0.001），表明 AICAR 的血管扩张作用对子宫循环是选择性的。此外，在正常氧小鼠中，用 Compound C 抑制 AMPK 的药理学抑制减少了子宫动脉直径并增加了子宫动脉收缩性，这表明生理水平的 AMPK 激活对于健康妊娠中的血管舒张是必需的。双向方差分析表明，缺氧降低了子宫动脉和胎盘的 AMPK 激活，与载体相比，AICAR 增加了这些组织中的 AMPK 激活。这些发现为进一步研究药理学 AMPK 激活治疗胎儿生长受限的效用提供了支持。
