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

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $678,441

## Abstract

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.

## Key facts

- **NIH application ID:** 10744376
- **Project number:** 2R01HD088590-06
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Colleen Glyde Julian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $678,441
- **Award type:** 2
- **Project period:** 2016-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10744376

## Citation

> US National Institutes of Health, RePORTER application 10744376, Effects of chronic hypoxia and AMPK activation on uteroplacental perfusion, placental metabolism and the regulation of fetal growth (2R01HD088590-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10744376. Licensed CC0.

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