# Uterine Vascular Adaptation to Pregnancy and Chronic Hypoxia

> **NIH NIH P01** · LOMA LINDA UNIVERSITY · 2020 · $122,760

## Abstract

PROJECT SUMMARY (Project I)
The striking increase of uterine blood flow during pregnancy is essential both for optimal growth of
the fetus and cardiovascular well-being of the mother. Maladaptation of the uteroplacental
circulation during gestation is associated with high incidence of clinical complications including
preeclampsia and fetal intrauterine growth restriction. Large-conductance Ca2+-activated K+
(BKca) channels play a critical role in regulating uterine blood flow in pregnancy. Recent studies in
sheep demonstrated that pregnancy and steroid hormones caused a significant increase in BKCa
β1 subunit resulting in increased β1: subunit stoichiometry and heightened BKCa channel activity
in uterine arteries. Chronic hypoxia during gestation abrogated these changes. Yet the molecular
mechanisms remain unknown. Our preliminary studies showed that pregnancy and steroid
hormones caused a decrease in DNA methylation at the β1 gene promoter. DNA methylation is a
chief mechanism in epigenetic repression of gene expression patterns, and recent studies suggest
a robust mechanism of ten-eleven translocation 1-3 (TET1-3) proteins in active DNA
demethylation. Preliminary studies suggested that pregnancy and steroid hormones increased
TET1-2 expression in uterine arteries. These findings lead to the proposed studies of a highly
novel mechanism testing the hypothesis that steroid hormone-induced, epigenetic-mediated
dynamic changes of DNA methylation and demethylation play a key role in regulating expression
and function of BKca channels in uterine vascular adaptation to pregnancy and chronic hypoxia.
Three specific aims will determine whether: 1) steroid hormone-mediated promoter demethylation
and BKca β1 gene up-regulation play a causal role in increased BKca channel function in uterine
arteries in pregnancy, 2) steroid hormones increase the expression of TET1-3 proteins in uterine
arteries, and 3) steroid hormone-mediated up-regulation of TET1-3 plays a causal role in active
DNA demethylation and the β1 gene reactivation in pregnancy. The results will significantly advance
our knowledge in molecular mechanisms of uteroplacental adaptation to pregnancy and improve our
understanding of pathophysiological mechanisms underlying maladaptation of uteroplacental
circulation and pregnancy complications associated with chronic hypoxia. They will also have a
broad impact in understanding of molecular mechanisms in regulating BKca channel activity and
vascular function in physiology and pathophysiology.

## Key facts

- **NIH application ID:** 9855055
- **Project number:** 5P01HD083132-05
- **Recipient organization:** LOMA LINDA UNIVERSITY
- **Principal Investigator:** Lubo Zhang
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $122,760
- **Award type:** 5
- **Project period:** — → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9855055

## Citation

> US National Institutes of Health, RePORTER application 9855055, Uterine Vascular Adaptation to Pregnancy and Chronic Hypoxia (5P01HD083132-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9855055. Licensed CC0.

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