# Benefits of nicotinamide in placental development and in preeclamsia

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $406,038

## Abstract

Summary/Abstract
The molecular mechanism of pathogenesis of preeclampsia (PE) is largely unknown, and effective prevention
and treatment strategies remain elusive. PE is a pregnancy-associated hypertensive condition and complicates
approximately one in 20 pregnancies in the US and is a leading cause of pregnancy-related maternal mortality
and neonatal morbidity/mortality worldwide. Endothelin-1 (ET-1) is a vasoconstrictive peptide of 21 residues,
and single nucleotide polymorphisms (SNPs) in EDN1, coding for a precursor for ET-1, are associated with PE.
Edn1H/+ mice in which Edn1 expression is elevated to 3X normal have normal blood pressure, despite elevated
circulating ET-1. However, Edn1H/+ dams develop full spectrum of PE-like phenotypes in their late pregnancy.
In addition, the embryos from Edn1H/+ dams, regardless of their Edn1 genotypes, lag in development during
early implantation stage with disoriented ectoplacental cones. We reported that nicotinamide (amide form of
vitamin B3, Nam), inhibitor of ET-1 downstream of ADP ribosylcyclase, ameliorates the PE-like phenotypes in
two separate mouse models of PE, and our preliminary data show that Nam decreases urinary albumin
excretion and increases the number of survival fetuses when Edn1H/+ dams were treated during the entire
pregnancy. These observations have led us to hypothesize that PE in Edn1H/+ dams originates from abnormal
placentation caused by a high maternal ET-1 expression at early implantation stage, and that Nam can correct
this damage and protect dams from later PE development. Accordingly, Specific Aim 1 will test this
hypothesis by dissociating early effects from later effects of Nam on PE of Edn1H/+dams by treatments with this
vitamin starting at different gestational stages and for different durations. Pregnancy outcomes including blood
pressure, urinary albumin and fetal number and weight will be determined at 18.5 day post coitus (dpc). In
addition, the expression of components of ET-1 system and Nam’s effects on them at implantation stage will
be examined. Specific Aim 2 will investigate the mechanism of effects of ET-1 and Nam on differentiation
from human trophoblast stem cells into designated trophoblast cells by using 2- and 3- dimension culture
system. Pharmacological dose of ET-1 alone, or ET-1 plus Nam will be added to the specific conditioned
medium. Cells will be examined by their morphology, motility, and expression of markers of different types of
trophoblasts. Specific Aim 3 will investigate the mechanism of effects of ET-1 and Nam on impaired uterine
decidualization and angiogenesis. The markers of endometrial stomal differentiation, the structure of blood
vessels and the expression of vascular endothelial growth factor (VEGF) in uteri at the implantation stage of
pregnancy will be examined. Primary cultured endometrial stromal cells will be treated with pharmacological
dose of ET-1 alone, or ET-1 plus Nam, and the markers of differentiation and the expressio...

## Key facts

- **NIH application ID:** 10831976
- **Project number:** 5R01HD101485-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Feng Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $406,038
- **Award type:** 5
- **Project period:** 2021-08-16 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831976

## Citation

> US National Institutes of Health, RePORTER application 10831976, Benefits of nicotinamide in placental development and in preeclamsia (5R01HD101485-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10831976. Licensed CC0.

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