# Uterine Arterial Spontaneous Transient Outward Currents in Pregnancy

> **NIH NIH R01** · LOMA LINDA UNIVERSITY · 2020 · $395,000

## Abstract

PROJECT SUMMARY
Uterine vascular adaptation with the striking increase of uterine blood flow during gestation is essential for
fetal development as well as for cardiovascular well-being of the mother. Although vasodilatation is of
critical importance in the adaptation of uterine circulation to pregnancy, the underlying mechanisms are not
fully understood. Spontaneous transient outward currents (STOCs) at physiological membrane potentials (
30-40 mV) of vascular smooth muscle cells fundamentally regulate vascular myogenic tone and blood flow
in an organ, as well as arterial pressure. Our preliminary studies in sheep revealed that pregnancy
significantly increased STOCs in uterine arterial smooth muscle cells, identifing an exciting regulatory target
in uterine vascular adaptation in gestation. STOCs are mainly mediated by large-conductance Ca2+-
activated K (BKca) channels. The BKca channel in vascular smooth muscle contains the channel-forming 
 +
subunit and up to four accessory β1 subunits that sense Ca2+ sparks via the opening of ryanodine
receptors. Our previous studies demonstrated a significant upregulation of BKβ1 subunit expression,
resulting in increased β1: subunit stoichiometry in uterine arteries of pregnant animals. This resulted from
a decrease in promoter methylation of the BKβ1 subunit gene in uterine arteries. Dynamic regulation of
DNA methylation and demethylation is a chief mechanism in epigenetic modifications of gene expression
pattern and biological function. Recent studies have suggested a robust mechanism of ten-eleven
translocation 1-3 (TET1-3) proteins in active DNA demethylation by converting 5-methylcytosine (5mC) into
5-hydroxymethylcytosine (5hmC). Our preliminary studies showed that pregnancy and steroid hormones
significantly increased TET1 and TET2 expression and 5hmC abundance at the BKβ1 promoter in uterine
arteries, suggesting a highly novel mechanism of hormone-mediated active DNA demethylation in uterine
vascular adaptation to pregnancy. In addition, the preliminary data suggested that pregnancy resulted in a
significant increase in Ca2+ sparks mediated by ryanodine receptors in uterine arteries. With these exciting
findings and many highly novel leads, we are now positioned to move the field forward significantly in a
manner by launching a new focus of research aiming at the understanding of molecular and epigenetic
mechanisms in the regulation of STOCs that are of fundamental importance in uterine arterial vasodilatation
during gestation. Thus, the proposed study will test the hypothesis that pregnancy upregulates BKβ1
subunit expression via TET-mediated DNA demethylation and increases ryanodine receptor-induced Ca2+
sparks, resulting in heightened STOCs in uterine vascular adaptation to pregnancy. The outcome of
proposed study will provide novel insights in molecular mechanisms of uteroplacental adaptation to
pregnancy, and will have a major impact in our understanding of pathophysiologic mechanisms und...

## Key facts

- **NIH application ID:** 9967087
- **Project number:** 5R01HL137649-04
- **Recipient organization:** LOMA LINDA UNIVERSITY
- **Principal Investigator:** Lubo Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $395,000
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967087

## Citation

> US National Institutes of Health, RePORTER application 9967087, Uterine Arterial Spontaneous Transient Outward Currents in Pregnancy (5R01HL137649-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9967087. Licensed CC0.

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