Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia

Feng Li, Tomofumi Fushima, Gen Oyanagi, H. W.Davin Townley-Tilson, Emiko Sato, Hironobu Nakada, Yuji Oe, John R. Hagaman, Jennifer Wilder, Manyu Li, Akiyo Sekimoto, Daisuke Saigusa, Hiroshi Sato, Sadayoshi Ito, J. Charles Jennette, Nobuyo Maeda, S. Ananth Karumanchi, Oliver Smithies, Nobuyuki Takahashi

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Preeclampsia (PE) complicates ∼5% of human pregnancies and is one of the leading causes of pregnancy-related maternal deaths. The only definitive treatment, induced delivery, invariably results in prematurity, and in severe early-onset cases may lead to fetal death. Many currently available antihypertensive drugs are teratogenic and therefore precluded from use. Nonteratogenic antihypertensives help control maternal blood pressure in PE, but results in preventing preterm delivery and correcting fetal growth restriction (FGR) that also occurs in PE have been disappointing. Here we show that dietary nicotinamide, a nonteratogenic amide of vitamin B3, improves the maternal condition, prolongs pregnancies, and prevents FGR in two contrasting mouse models of PE. The first is caused by endotheliosis due to excess levels in the mothers of a soluble form of the receptor for vascular endothelial growth factor (VEGF), which binds to and inactivates VEGF. The second is caused by genetic absence of Ankiryn-repeat-and-SOCS-box-containing-protein 4, a factor that contributes to the differentiation of trophoblast stem cells into the giant trophoblast cells necessary for embryo implantation in mice; its absence leads to impaired placental development. In both models, fetal production of ATP is impaired and FGR is observed. We show here that nicotinamide decreases blood pressure and endotheliosis in the mothers, probably by inhibiting ADP ribosyl cyclase (ADPRC), and prevents FGR, probably by normalizing fetal ATP synthesis via the nucleotide salvage pathway. Because nicotinamide benefits both dams and pups, it merits evaluation for preventing or treating PE in humans.

Original languageEnglish
Pages (from-to)13450-13455
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number47
DOIs
Publication statusPublished - 2016 Nov 22

Keywords

  • Fetal growth restriction
  • Nicotinamide
  • Placentation
  • Preeclampsia
  • sFLT1

ASJC Scopus subject areas

  • General

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