High altitude residence (HA, >2500 m) increases the frequency of preeclampsia (PreE) and intrauterine growth restriction (IUGR) 3-fold. Since hypoxia is a common cause, HA studies are uniquely positioned to evaluate the mechanistic role of hypoxia, discover new treatments, and alleviate the ?almost complete lack of drug development for obstetric indications? noted in PAR-13-389. Adenosine monophosphate kinase (AMPK) is a regulator of metabolic homeostasis that also affects vascular growth and function under hypoxia. We have shown that AMPK plays important roles in the regulation of human uterine artery (UtA) blood flow and fetal growth at HA, and that AMPK activation has vasodilator effects in isolated murine UtA that are potentiated by hypoxia. Our central hypothesis is that AMPK activation promotes vasodilation in the uteroplacental circulation in response to hypoxia to raise UtA blood flow and improve fetal growth at HA. Because hypoxia leads to epigenetic changes that alter the expression of genes regulating of AMPK activity and fetal growth, we propose that DNA methylation influences these AMPK-mediated processes. We present new murine and human data to show that hypoxia a) raises placental phosphorylated (P)- relative to total AMPK levels and the P- as well as the total protein levels of AMPK targets in thoracic aorta and placenta; b) increases the expression of key enzymes activating AMPK in UtA and placenta; and c) alters methylation-expression relationships of AMPK- signaling genes important for fetal growth. We will test our central hypothesis by determining: 1.
In Aim 1, the effect of HA pregnancy on AMPK signaling and its relationship to UtA blood flow and fetal growth in humans. We will recruit 102 healthy residents of low altitude (LA, 1600 m, n=53) or HA (3000 m, n=49); measure UtA blood flow and fetal biometry longitudinally; and determine the activation of AMPK, its upstream regulators and downstream targets, the expression levels and DNA methylation of relevant genes in peripheral blood mononuclear cells (PBMCs), and plasma levels of AMPK regulators. 2.
In Aim 2, the effects of hypoxia on AMPK activation in human myometrial artery (MA) and placenta, and on MA vasoreactivity. In women participating in Aim 1 who deliver by elective C-section (n=19/altitude), we will obtain myometrial biopsies and placentas to determine a) the activation, expression and DNA methylation status of AMPK, its well-established regulators and downstream targets; b) the effect of HA pregnancy on MA vasoreactivity; and c) whether hypoxia potentiates vasodilator effects of AMPK activation in MA. 3.
In Aim 3, the role of AMPK in regulating uteroplacental blood flow and fetal growth in response to hypoxia in mice. Pregnant mice housed at sea level (SL) or HA will be treated with the AMPK activator (AICAR), inhibitor (Compound C), or vehicle (control) for determining the separate and combined effects of hypoxia and AMPK activation on AMPK signaling in UtA, placental and fetal tissues; UtA vascular reactivity and blood flow; and fetal growth.

Public Health Relevance

No factors are more important to public health than those determining the health of the mother and her baby in utero yet few treatments for pregnancy-disorders have been introduced in the past 20 years. Since AMPK activity can be modulated by numerous substances, one of which (metformin) has been shown to be safe for use in human pregnancy, the proposed work has the potential to accelerate new interventions for improving UtA blood flow and alleviating or preventing IUGR or PreE.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD088590-02
Application #
9327023
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Tsilou, Katerina
Project Start
2016-08-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$322,663
Indirect Cost
$115,163
Name
University of Colorado Denver
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Schmidt, Sydney M L; Usselman, Charlotte W; Martinek, Eric et al. (2018) Activity of muscle sympathetic neurons during normotensive pregnancy. Am J Physiol Regul Integr Comp Physiol 314:R153-R160
Lorca, Ramón A; Wakle-Prabagaran, Monali; Freeman, William E et al. (2018) The large-conductance voltage- and Ca2+ -activated K+ channel and its ?1-subunit modulate mouse uterine artery function during pregnancy. J Physiol 596:1019-1033
Li, Yingchun; Lorca, Ramón A; Su, Emily J (2018) Molecular and cellular underpinnings of normal and abnormal human placental blood flows. J Mol Endocrinol 60:R9-R22
Julian, Colleen G (2017) Epigenomics and human adaptation to high altitude. J Appl Physiol (1985) 123:1362-1370
Song, Anren; Zhang, Yujin; Han, Leng et al. (2017) Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent. Nat Commun 8:14108
Moore, Lorna G (2017) Measuring high-altitude adaptation. J Appl Physiol (1985) 123:1371-1385
Lorca, Ramón A; Ma, Xiaofeng; England, Sarah K (2017) The unique N-terminal sequence of the BKCa channel ?-subunit determines its modulation by ?-subunits. PLoS One 12:e0182068
Charkoudian, Nisha; Usselman, Charlotte W; Skow, Rachel J et al. (2017) Muscle sympathetic nerve activity and volume-regulating factors in healthy pregnant and nonpregnant women. Am J Physiol Heart Circ Physiol 313:H782-H787
Moore, Lorna G (2017) Human Genetic Adaptation to High Altitudes: Current Status and Future Prospects. Quat Int 461:4-13
Crawford, Jacob E; Amaru, Ricardo; Song, Jihyun et al. (2017) Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans. Am J Hum Genet 101:752-767