Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado.
Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado.
Am J Physiol Heart Circ Physiol. 2020 Jul 1;319(1):H203-H212. doi: 10.1152/ajpheart.00644.2019. Epub 2020 Jun 5.
High-altitude (>2,500 m) residence increases the incidence of intrauterine growth restriction (IUGR) due, in part, to reduced uterine artery blood flow and impaired myometrial artery (MA) vasodilator response. A role for the AMP-activated protein kinase (AMPK) pathway in protecting against hypoxia-associated IUGR is suggested by genomic and transcriptomic studies in humans and functional studies in mice. AMPK is a hypoxia-sensitive metabolic sensor with vasodilatory properties. Here we hypothesized that AMPK-dependent vasodilation was increased in MAs from high versus low-altitude (<1,700 m) Colorado women with appropriate for gestational age (AGA) pregnancies and reduced in IUGR pregnancies regardless of altitude. Vasoreactivity studies showed that, in AGA pregnancies, MAs from high-altitude women were more sensitive to vasodilation by activation of AMPK with A769662 due chiefly to increased endothelial nitric oxide production, whereas MA responses to AMPK activation in the low-altitude women were endothelium independent. MAs from IUGR compared with AGA pregnancies had blunted vasodilator responses to acetylcholine at high altitude. We concluded that ) blunted vasodilator responses in IUGR pregnancies confirm the importance of MA vasodilation for normal fetal growth and ) the increased sensitivity to AMPK activation in AGA pregnancies at high altitude suggests that AMPK activation helped maintain MA vasodilation and fetal growth. These results highlight a novel mechanism for vasodilation of MAs under conditions of chronic hypoxia and suggest that AMPK activation could provide a therapy for increasing uteroplacental blood flow and improving fetal growth in IUGR pregnancies. Intrauterine growth restriction (IUGR) impairs infant well- being and increases susceptibility to later-in-life diseases for mother and child. Our study reveals a novel role for AMPK in vasodilating the myometrial artery (MA) from women residing at high altitude (>2,500 m) with appropriate for gestational age pregnancies but not in IUGR pregnancies at any altitude.
高海拔（>2500 米）居住会增加宫内生长受限（IUGR）的发生率，部分原因是子宫动脉血流减少和子宫肌层动脉（MA）舒张反应受损。基因组和转录组研究以及在小鼠中的功能研究表明，AMP 激活蛋白激酶（AMPK）通路在保护与缺氧相关的 IUGR 中发挥作用。AMPK 是一种对缺氧敏感的代谢传感器，具有血管舒张特性。在这里，我们假设与低海拔（<1700 米）科罗拉多州具有适当胎龄（AGA）妊娠的女性相比，高海拔女性的 MA 中 AMPK 依赖性血管舒张增加，而无论海拔如何，IUGR 妊娠的 MA 中 AMPK 依赖性血管舒张减少。血管反应性研究表明，在 AGA 妊娠中，高海拔女性的 MA 对 A769662 激活 AMPK 的血管舒张更敏感，主要是由于内皮一氧化氮产生增加，而低海拔女性的 MA 对 AMPK 激活的反应是内皮非依赖性的。与 AGA 妊娠相比，IUGR 妊娠的 MA 对乙酰胆碱的血管舒张反应减弱。我们得出结论，）IUGR 妊娠中血管舒张反应减弱证实了 MA 血管舒张对正常胎儿生长的重要性，）高海拔 AGA 妊娠中对 AMPK 激活的敏感性增加表明 AMPK 激活有助于维持 MA 血管舒张和胎儿生长。这些结果突出了慢性缺氧条件下 MA 血管舒张的一种新机制，并表明 AMPK 激活可能为增加 IUGR 妊娠中的胎盘血流和改善胎儿生长提供一种治疗方法。宫内生长受限（IUGR）会损害婴儿的健康，并增加母婴日后患病的易感性。我们的研究揭示了 AMPK 在高海拔（>2500 米）有适当胎龄妊娠的女性中舒张子宫肌层动脉（MA）的新作用，但在任何海拔的 IUGR 妊娠中没有这种作用。
