# Project 003 - Lorena Amaral

> **NIH NIH P20** · UNIVERSITY OF MISSISSIPPI MED CTR · 2024 · $235,872

## Abstract

Preeclampsia (PE) affects 5-7% of all pregnancies in the U.S and 30% of hypertensive disorders in pregnancy 
are caused by chronic hypertension (HTN) prior to pregnancy which increases the risk of superimposed PE 
(SIPE). Despite being a leading cause of maternal death and perinatal morbidity, the mechanisms responsible 
for PE and SIPE are unclear. Healthy normal pregnancy (NP) is associated with elevations in progesterone 
and T helper 2 (TH2)/uterine natural killer cells (NK cells), favoring immunotolerance of the fetus. Activated 
lymphocytes during NP express progesterone receptors, which stimulate a protein called Progesterone Induced 
Blocking Factor (PIBF). PIBF increases during NP and stimulates interleukin-4 and TH2 cells (IL- 4/TH2) cells, 
both of which are reduced during PE. PIBF also decreases the deleterious effects of cytolytic NK cells in 
murine pregnancy. Importantly, we showed that PE is a progesterone deficient state that is associated with an 
imbalance between TH1/TH2 cells, NK cells, and inflammatory cytokines that lead to endothelial dysfunction, 
intrauterine growth restriction (IUGR) and HTN. We also reported that the increase in TH1 cells contributes to 
production of agonistic angiotensin 1 receptor autoantibody (AT1-AA) by B cells, increases in endothelin (ET1) and soluble fms-like tyrosine kinase-1 (sFlt-1), all of which are associated with PE and SIPE. Even though 
PIBF is essential for maintenance of NP, a role for PIBF to stimulate IL-4/TH2 as a mechanism to improve the 
pathophysiology associated with PE or SIPE has not been studied. My recent published data indicate that PIBF 
attenuates HTN and improves fetal IUGR in response to placental ischemia in the reduced uterine perfusion 
pressure rat model of PE. In addition, my exciting clinical data show that PE patients have reduced PIBF, and 
supplementation with progesterone (as 17-hydroxyprogesterone caproate (17-OHPC)) improves TH1/TH2 ratio. 
Although PIBF stimulates TH2 lymphocytes secreting IL-4, whether 17-OHPC stimulates PIBF to protect 
against PE or SIPE is unknown. Thus my hypothesis is that an increase in uterine artery resistance index leads 
to a decrease in PIBF and IL-4 leading to increased TH1, NK and AT1-AA, causing changes in vasoactive 
factors (increased sFlt-1, ET-1; decreased nitric oxide), thus contributing to SIPE with exacerbation of HTN in 
the mother and IUGR in the offspring. This hypothesis will be tested using the pregnant Dahl salt-sensitive (DS) 
rat, a model of superimposed PE, and will utilize a combination of in vitro and in vivo approaches to examine 
the following specific aims: Aim 1: To test the hypothesis that 17-OHPC supplementation in the pregnant DS 
rat, a model of SIPE, reduces BP and stimulates PIBF, reduces inflammation, AT1-AA, sFlt-1, ET-1, improves 
endothelial-dependent relaxation, and prevents development of IUGR in offspring. Aim 2: To test the 
hypothesis that PIBF supplementation in pregnant DS rat, a model ...

## Key facts

- **NIH application ID:** 11060656
- **Project number:** 5P20GM121334-08
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Lorena M Amaral
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $235,872
- **Award type:** 5
- **Project period:** 2024-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11060656

## Citation

> US National Institutes of Health, RePORTER application 11060656, Project 003 - Lorena Amaral (5P20GM121334-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11060656. Licensed CC0.

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