# Hypertension, Inflammation, and Vascular Function

> **NIH NIH R01** · UNIVERSITY OF MISSISSIPPI MED CTR · 2020 · $352,300

## Abstract

PROJECT SUMMARY
Preeclampsia (PE) is estimated to affect 5-7% of all pregnancies in the U.S. The initiating event in PE is
postulated to involve reduced placental perfusion that leads to widespread chronic immune activation and
maternal vascular dysfunction. Despite its position as a leading cause of maternal death and major contributor
to maternal and perinatal morbidity, there is no effective drug treatment to prevent preeclampsia, and current
management therapies have significant limitations. At present, the only effective treatment for preeclampsia is
early delivery of the baby and placenta. Based on recent studies and on preliminary data presented in this
application, we propose that the NLRP3 inflammasome is a novel therapeutic target for the treatment of PE.
Recent studies have shown that NLRP3 protein expression is increased in women with PE. Our compelling
preliminary data indicating that chronic administration of a NLRP3 inhibitor significantly improves blood pressure
and intrauterine growth restriction in response to reduced uterine perfusion pressure (RUPP) supports the
concept that modulation of the NLRP3 inflammasome may protect against the progression of PE. Additional
preliminary findings demonstrate that inhibition of NLRP3 decreases T-helper 17 cells (TH17s) and cytolytic NK
cell (cNK) activation, two important immune factors implicated in the pathophysiology of PE. We also provide
evidence that suggest the NLRP3/caspase-1/IL-1β pathway modulate IL-33 signaling to induce immune
dysfunction associated with PE in pregnant rats. Based on recent studies and on preliminary data presented in
this application, we propose that inhibition of NLRP3 activation may provide novel therapeutic approaches for
the treatment of PE. Our overall hypothesis is that placental ischemia activates NLRP3 and increases
caspase-1/IL-1β which in turn leads to decreased IL-33 and increased TH17s and cNK activation to cause
vascular and renal dysfunction, hypertension, and intrauterine growth restriction. To test this hypothesis,
we will use an established animal model of PE: Reduced Uterine Perfusion Pressure (RUPP) model of placental
ischemia. We will also utilize physiological and pharmacological approaches complemented with molecular,
biochemical, and in vivo techniques to address vertically integrated specific aims. We are confident that our
proposed studies will provide new and important information regarding the pathophysiological mechanisms
linking placental ischemia and maternal hypertension and intrauterine growth restriction in PE, but more
importantly help identify novel therapeutic targets for the treatment of PE.

## Key facts

- **NIH application ID:** 9940319
- **Project number:** 1R01HL151407-01
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Denise Creshun Cornelius
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,300
- **Award type:** 1
- **Project period:** 2020-05-19 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940319

## Citation

> US National Institutes of Health, RePORTER application 9940319, Hypertension, Inflammation, and Vascular Function (1R01HL151407-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9940319. Licensed CC0.

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