# Maternal vascular responses to extracellular mitochondrial DNA during pregnancy

> **NIH NIH R01** · UNIVERSITY OF NORTH TEXAS HLTH SCI CTR · 2021 · $527,749

## Abstract

PROJECT SUMMARY
Hypertensive disorders of pregnancy, including preeclampsia, are among the leading causes of maternal
deaths. It has been suggested that in preeclampsia, placental hypoperfusion/ischemia results in release of pro-
inflammatory factors that interact with the maternal vascular wall to induce maternal vascular dysfunction and
hypertension. The molecular pathways linking placenta-derived factors and maternal vascular dysfunction are
not understood. Furthermore, the mechanisms determining the release of placenta-derived factors in the
maternal circulation are underexplored. The proposed studies will address these knowledge gaps by testing
the role of extracellular mitochondrial DNA (mtDNA) as a novel link between maternal vascular dysfunction and
placental ischemia, common features of preeclampsia. Plasma from women with preeclampsia has increased
circulating cell-free mtDNA, which has been shown to be immunogenic and pro-inflammatory in various
inflammatory conditions. Furthermore, clinical studies have demonstrated a positive association between
circulating mtDNA and the risk of developing preeclampsia. Here, we propose that circulating cell-free mtDNA
derived from the placenta is a major contributor to maternal vascular dysfunction in preeclampsia, due in part
to its effects on Toll-like receptor 9 (TLR-9). Aim 1: we will determine a molecular mechanism linking
extracellular mtDNA with maternal vascular dysfunction during pregnancy. We hypothesize that vascular
exposure to extracellular mtDNA will induce an increase in maternal vascular tone through activation of TLR-9
signaling. This hypothesis will be tested using an integrative approach involving isolated maternal arteries,
vascular cells, and an in vivo mtDNA challenge in healthy non-pregnant and pregnant rats. Aim 2: we will
determine a potential mechanism by which placental hypoxia induces release of mtDNA. We will test the
hypothesis that placental hypoxia causes increased generation of reactive oxygen species, which in turn
triggers the release of mtDNA into the extracellular space by inducing cell death and increasing autophagy. To
address this hypothesis, we will use human trophoblast cells and rat placental explants. Aim 3: we will
determine whether increased circulating mtDNA is involved in the pathogenesis or maintenance of the
maternal cardiovascular syndrome in preeclampsia. We will test the hypothesis that increased circulating
mtDNA triggers the maternal cardiovascular syndrome in an animal model with placental ischemia that mimics
clinical end-points of preeclampsia and has higher concentrations of circulating mtDNA compared to normal
pregnant rats. This research may have a translational impact because it will provide a pre-clinical platform for
the development of pharmacological strategies to reduce mtDNA release, neutralize extracellular mtDNA, or
inhibit TLR-9 in those women who have high concentrations of circulating cell-free mtDNA during pregnancy.

## Key facts

- **NIH application ID:** 10076858
- **Project number:** 5R01HL146562-02
- **Recipient organization:** UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
- **Principal Investigator:** Styliani Goulopoulou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $527,749
- **Award type:** 5
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076858

## Citation

> US National Institutes of Health, RePORTER application 10076858, Maternal vascular responses to extracellular mitochondrial DNA during pregnancy (5R01HL146562-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10076858. Licensed CC0.

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