# Chronic hypoxia, AMPK activation and uterine artery blood flow

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $322,663

## Abstract

Project Summary
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...

## Key facts

- **NIH application ID:** 9925655
- **Project number:** 5R01HD088590-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Colleen Glyde Julian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $322,663
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925655

## Citation

> US National Institutes of Health, RePORTER application 9925655, Chronic hypoxia, AMPK activation and uterine artery blood flow (5R01HD088590-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9925655. Licensed CC0.

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