Effects of chronic hypoxia and AMPK activation on uteroplacental perfusion, placental metabolism and the regulation of fetal growth

慢性缺氧和AMPK激活对子宫胎盘灌注、胎盘代谢及胎儿生长调节的影响

基本信息

批准号：
10744376
负责人：
Colleen Glyde Julian
金额：
$ 67.84万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2028-05-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY The hypoxia of high-altitude (HA, >2500 m) increases the frequency of fetal growth restriction (FGR) three-fold. The normal pregnancy rise in blood flow to the uteroplacental circulation (termed “uterine” here) is also reduced in FGR at HA or at low altitude, but lower uterine blood flow is not solely responsible for FGR because O2 supply still exceeds fetal O2 consumption, even at HA. Thus, the mechanisms by which lower uterine blood flow reduces fetal growth and their temporal relationship remain unclear. Our prior work implicates AMPK in the regulation of uterine vascular function, blood flow, and fetal growth, and our preliminary data show that FGR vs. appropriate for gestational age (AGA) pregnancies in La Paz, Bolivia (3850 m) have lower third-trimester uterine blood flow; greater placental AMPK activation, suppressed mitochondrial oxidative metabolism, and metabolite profiles supporting impaired fatty acid and amino acid metabolism. We propose human and sheep studies to be conducted under chronic maternal hypoxia in order to determine whether placental AMPK signaling serves as a nexus between uteroplacental perfusion and placental metabolism to regulate fetal growth through its dual role as a potent vasodilator and metabolic sensor. In HA residents with AGA or FGR pregnancies women at unlabored C-section, we will measure blood flows, perform four-vessel sampling on both sides of the placenta, collect placental and human uteroplacental and fetoplacental arteries regulating blood flow for vasoreactivity studies, and conduct biochemical assays. Because vasodilation is impaired in FGR, we will test whether pharmacologic mediated modulators of mitochondrial oxidative metabolism and redox status restore impaired AMPK- vasorelaxation.Since access to human blood vessels and placenta are only available at delivery, we will perform parallel studies in a sheep model of hypoxia-associated FGR in order to measure these same variables but also with metabolic tracers both before and after FGR (i.e. at mid- and late-gestation respectively) in order to identify when uterine O2 supply decreases, and test the temporal relationship between O2 supply, O2 consumption, nutrient uptake, and fetoplacental metabolism relative to the initiation of FGR. As in the human studies, we will also assess the effects of AMPK activation on uterine vasoreactivity and placental nutrient metabolism, and test whether restoring mitochondrial oxidative metabolism improves vasodilation in key uterine resistance vessels. The proposed studies will enable our understanding to move beyond the conventional idea that insufficient fetal oxygenation triggers FGR to one in which we know when and how the hypoxia-associated FGR develops. Such information is essential for refining therapeutic strategies for restoring fetal growth under conditions of hypoxia, a goal that has, to date, proven elusive.

项目概要高海拔（HA，>2500 m）的缺氧使胎儿生长受限（FGR）的发生率增加三倍。正常妊娠时流向子宫胎盘循环（此处称为“子宫”）的血流量也会减少在 HA 或低海拔地区发生 FGR，但子宫血流量降低并不是造成 FGR 的唯一原因，因为氧气供应即使在 HA 时，仍然超过胎儿的 O2 消耗量。因此，子宫血流量减少的机制。我们之前的工作表明 AMPK 参与了胎儿生长的调节。子宫血管功能、血流量和胎儿生长，我们的初步数据表明 FGR 与适当的玻利维亚拉巴斯 (3850 m) 的孕龄 (AGA) 妊娠的妊娠晚期子宫血流量较低；更大的胎盘 AMPK 激活，抑制线粒体氧化代谢和代谢特征我们建议对人类和绵羊进行研究以支持受损的脂肪酸和氨基酸代谢。在母亲慢性缺氧的情况下进行，以确定无论胎盘 AMPK 信号传导作为子宫胎盘灌注和胎盘代谢之间的联系，通过其双重作用调节胎儿生长作为一种有效的血管舒张剂和代谢传感器，适用于患有 AGA 或 FGR 妊娠的 HA 居民。未分娩的剖腹产，我们将测量血流量，对胎盘两侧进行四血管取样，收集调节血流的胎盘和人类子宫胎盘和胎儿胎盘动脉以进行血管反应研究，并进行生化测定，因为 FGR 中血管舒张受损，我们将测试是否。药理学介导的线粒体氧化代谢和氧化还原状态的调节剂可恢复受损的 AMPK- 血管舒张。由于只有在分娩时才能接触人体血管和胎盘，因此我们将在缺氧相关 FGR 的绵羊模型中进行平行研究，以测量这些相同的结果变量，还包括 FGR 之前和之后的代谢示踪剂（即分别在妊娠中期和晚期）为了确定子宫 O2 供应何时减少，并测试 O2 供应、O2 之间的时间关系与人类 FGR As 起始相关的消耗、营养吸收和胎儿胎盘代谢。研究中，我们还将评估 AMPK 激活对子宫血管反应性和胎盘营养的影响代谢，并测试恢复线粒体氧化代谢是否可以改善关键子宫的血管舒张所提出的研究将使我们的理解超越传统的想法。胎儿氧合不足会触发 FGR，我们知道何时以及如何与缺氧相关 FGR 的发展对于完善恢复胎儿生长的治疗策略至关重要。迄今为止，这一目标已被证明难以实现。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Measuring high-altitude adaptation.

测量高海拔适应能力。

DOI：
10.1152/japplphysiol.00321.2017
发表时间：
2017-11-01
期刊：
Journal of applied physiology
影响因子：
3.3
作者：
L. Moore
通讯作者：
L. Moore

Activity of muscle sympathetic neurons during normotensive pregnancy.

正常血压妊娠期间肌肉交感神经元的活动。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Schmidt, Sydney M L;Usselman, Charlotte W;Martinek, Eric;Stickland, Michael K;Julian, Colleen G;Chari, Radha;Khurana, Rshmi;Davidge, Sandra T;Davenport, Margie H;Steinback, Craig D
通讯作者：
Steinback, Craig D

AMPK activation in pregnant human myometrial arteries from high-altitude and intrauterine growth-restricted pregnancies.

来自高海拔和宫内生长受限妊娠的妊娠人子宫肌动脉中的 AMPK 激活。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Lorca, Ramón A;Matarazzo, Christopher J;Bales, Elise S;Houck, Julie A;Orlicky, David J;Euser, Anna G;Julian, Colleen G;Moore, Lorna G
通讯作者：
Moore, Lorna G

Protein kinase A facilitates relaxation of mouse ileum via phosphorylation of neuronal nitric oxide synthase.

蛋白激酶 A 通过神经元一氧化氮合酶的磷酸化促进小鼠回肠的松弛。