Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia.
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.
Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC 27599.
Feng
F
Li
Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan.
Tomofumi
T
Fushima
Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan.
Gen
G
Oyanagi
Department of Cell and Developmental Biology, The University of North Carolina, Chapel Hill, NC 27599.
H W Davin
HW
Townley-Tilson
Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan.|Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University, Sendai 980-8574, Japan.
Emiko
E
Sato
Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan.
Hironobu
H
Nakada
Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University, Sendai 980-8574, Japan.
Yuji
Y
Oe
Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC 27599.
John R
JR
Hagaman
Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC 27599.
Jennifer
J
Wilder
Department of Cell and Molecular Physiology, The University of North Carolina, Chapel Hill, NC 27599.
Manyu
M
Li
Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan.|Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University, Sendai 980-8574, Japan.
Akiyo
A
Sekimoto
Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan.
Daisuke
D
Saigusa
Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan.|Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University, Sendai 980-8574, Japan.
Hiroshi
H
Sato
Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University, Sendai 980-8574, Japan.
Sadayoshi
S
Ito
Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC 27599.
J Charles
JC
Jennette
Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC 27599.
Nobuyo
N
Maeda
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
S Ananth
SA
Karumanchi
Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC 27599; ntakaha@m.tohoku.ac.jp oliver_smithies@med.unc.edu.
Oliver
O
Smithies
Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC 27599; ntakaha@m.tohoku.ac.jp oliver_smithies@med.unc.edu.|Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8578, Japan.|Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University, Sendai 980-8574, Japan.|Department of Cell and Molecular Physiology, The University of North Carolina, Chapel Hill, NC 27599.
Nobuyuki
N
Takahashi
D000022:Abortion, Spontaneous / Q000097:blood / Q000503:physiopathology; D000419:Albuminuria / Q000097:blood / Q000150:complications / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D020964:Embryo Loss / Q000188:drug therapy / Q000517:prevention & control; D005260:Female; D005317:Fetal Growth Retardation / Q000097:blood / Q000188:drug therapy; D006973:Hypertension / Q000097:blood / Q000150:complications / Q000503:physiopathology; D007668:Kidney / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008810:Mice, Inbred C57BL; D009536:Niacinamide / Q000494:pharmacology / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000072483:Placenta Growth Factor / Q000097:blood; D011225:Pre-Eclampsia / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D011256:Pregnancy Outcome; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000378:metabolism; D014599:Uterus / Q000187:drug effects / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood / Q000378:metabolism
C530435:Asb4 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D009536:Niacinamide; D040281:Vascular Endothelial Growth Factor Receptor-1
fetal growth restriction; nicotinamide; placentation; preeclampsia; sFLT1