# Vasopressin and Preeclampsia: Early Mechanisms for Prevention

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $394,723

## Abstract

Preeclampsia (PreE) is a prevalent hypertensive disorder in pregnancy and is a leading cause of worldwide
obstetric mortality with 76,000 maternal and 500,000 neonatal deaths yearly. Due to the unclear early
pregnancy etiology of PreE, prevention of PreE is limited to daily baby aspirin which may only modestly
prevent PreE. A polymorphism in the gene encoding Regulator of G-Protein Signaling (RGS)-2 is associated
with an increased risk for preeclampsia. RGS2 is a member of the B/R4 family of RGS proteins which acts as
an endogenous inhibitor of Gq-calcium second-messenger signaling, a common pathogenic pathway for
many PreE related hormones such as arginine vasopressin (AVP). Betamethasone (BTMZ) is commonly given
to women at risk of preterm delivery to prevent neonatal morbidities. Our preliminary data and the literature
suggest that steroids like BMTZ can induce RGS2, thereby turning off the excessive pathogenic Gq-calcium
signaling seen in PreE. Together these data lead us to the overall hypothesis that BMTZ prevents PreE by
restoring placental RGS2 signaling and decreasing the excessive Gq-calcium signaling that has been
associated with PreE related placental dysfunction. The overall objectives of the current proposal are (i) to
evaluate the impact excessive Gq signaling upon placental trophoblast function and preeclampsia
phenotypes, and (ii) demonstrate that BMTZ increases RGS2 activity leading to decreased Gq-calcium
signaling thereby preventing PreE. Aim 1 will examine the role of excess placental Gαq signaling on placental
dysfunction and PreE in a placental specific hm3Dq (Gαq-activating) DREDD receptor mouse model.
Consistent with this, we will test that reduced RGS2 results in PreE through the excessive Gαq signaling in a
feto-placental RGS2 reduction mouse model (WT dams X RGS2-KO males). In isolated total trophoblasts from
these mouse models and in primary human preeclamptic placental tissues, we will study if increased calcium
release leads to the poor trophoblast migration consistent with PreE. Aim 2 will test our hypothesis that the
observed reduction in RGS2 in PreE is due to reduced trophoblast cAMP-CREB signaling as will be tested in
(AVP)-induced HTR-8/svNeo cells and primary human trophoblasts from PreE pregnancies. We will examine if
this reduction in cAMP-CREB-RGS2 signaling will be reversed by treatment with BMTZ in i) AVP-induced
HTR-8/svNeo cells, ii) primary human trophoblasts clinically exposed to BMTZ and iii) in our chronic infusion of
vasopressin (CIV) mouse model of PreE. Together these studies will greatly clarify a potential causal role of
RGS2 in the pathogenesis of preeclampsia, physiological mechanisms controlling RGS2 expression in
placental trophoblasts and the possible novel use of BMTZ in the prevention of preeclampsia.

## Key facts

- **NIH application ID:** 9853040
- **Project number:** 5R01HD089940-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** MARK K SANTILLAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,723
- **Award type:** 5
- **Project period:** 2019-01-23 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853040

## Citation

> US National Institutes of Health, RePORTER application 9853040, Vasopressin and Preeclampsia: Early Mechanisms for Prevention (5R01HD089940-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9853040. Licensed CC0.

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