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Original Article

Causative Effects of Genetically Determined High Maternal/Fetal Endothelin-1 on Preeclampsia-Like Conditions in MiceNovelty and Significance

Feng Li, Masao Kakoki, Marcela Smid, Kim Boggess, Jennifer Wilder, Sylvia Hiller, Carol Bounajim, Scott E. Parnell, Kathleen K. Sulik, Oliver Smithies, Nobuyo Maeda-Smithies
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https://doi.org/10.1161/HYPERTENSIONAHA.117.10849
Hypertension. 2018;71:894-903
Originally published April 2, 2018
Feng Li
From the Department of Pathology and Laboratory Medicine (F.L., M.K., J.W., S.H., O.S., N.M.-S.), Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (K.B.), School of Medicine (C.B.), and Department of Cell Biology and Physiology (S.E.P., K.K.S.), University of North Carolina; and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City (M.S.).
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Masao Kakoki
From the Department of Pathology and Laboratory Medicine (F.L., M.K., J.W., S.H., O.S., N.M.-S.), Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (K.B.), School of Medicine (C.B.), and Department of Cell Biology and Physiology (S.E.P., K.K.S.), University of North Carolina; and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City (M.S.).
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Marcela Smid
From the Department of Pathology and Laboratory Medicine (F.L., M.K., J.W., S.H., O.S., N.M.-S.), Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (K.B.), School of Medicine (C.B.), and Department of Cell Biology and Physiology (S.E.P., K.K.S.), University of North Carolina; and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City (M.S.).
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Kim Boggess
From the Department of Pathology and Laboratory Medicine (F.L., M.K., J.W., S.H., O.S., N.M.-S.), Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (K.B.), School of Medicine (C.B.), and Department of Cell Biology and Physiology (S.E.P., K.K.S.), University of North Carolina; and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City (M.S.).
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Jennifer Wilder
From the Department of Pathology and Laboratory Medicine (F.L., M.K., J.W., S.H., O.S., N.M.-S.), Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (K.B.), School of Medicine (C.B.), and Department of Cell Biology and Physiology (S.E.P., K.K.S.), University of North Carolina; and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City (M.S.).
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Sylvia Hiller
From the Department of Pathology and Laboratory Medicine (F.L., M.K., J.W., S.H., O.S., N.M.-S.), Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (K.B.), School of Medicine (C.B.), and Department of Cell Biology and Physiology (S.E.P., K.K.S.), University of North Carolina; and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City (M.S.).
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Carol Bounajim
From the Department of Pathology and Laboratory Medicine (F.L., M.K., J.W., S.H., O.S., N.M.-S.), Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (K.B.), School of Medicine (C.B.), and Department of Cell Biology and Physiology (S.E.P., K.K.S.), University of North Carolina; and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City (M.S.).
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Scott E. Parnell
From the Department of Pathology and Laboratory Medicine (F.L., M.K., J.W., S.H., O.S., N.M.-S.), Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (K.B.), School of Medicine (C.B.), and Department of Cell Biology and Physiology (S.E.P., K.K.S.), University of North Carolina; and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City (M.S.).
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Kathleen K. Sulik
From the Department of Pathology and Laboratory Medicine (F.L., M.K., J.W., S.H., O.S., N.M.-S.), Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (K.B.), School of Medicine (C.B.), and Department of Cell Biology and Physiology (S.E.P., K.K.S.), University of North Carolina; and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City (M.S.).
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Oliver Smithies
From the Department of Pathology and Laboratory Medicine (F.L., M.K., J.W., S.H., O.S., N.M.-S.), Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (K.B.), School of Medicine (C.B.), and Department of Cell Biology and Physiology (S.E.P., K.K.S.), University of North Carolina; and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City (M.S.).
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Nobuyo Maeda-Smithies
From the Department of Pathology and Laboratory Medicine (F.L., M.K., J.W., S.H., O.S., N.M.-S.), Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (K.B.), School of Medicine (C.B.), and Department of Cell Biology and Physiology (S.E.P., K.K.S.), University of North Carolina; and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City (M.S.).
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Abstract

Endothelin-1 (ET-1) is implicated in the pathophysiology of preeclampsia. An association between an EDN1 gene polymorphism with high ET-1 and preeclampsia was reported in humans, but their cause and effect relationships have not been defined. We examined the pregnancy effects in mice with a modified Edn1 allele that increases mRNA stability and thus ET-1 production. Heterozygous Edn1H/+ females showed no obvious abnormalities before pregnancy, but when mated with wild-type (WT) males developed a full spectrum of preeclampsia-like phenotypes, including increased systolic blood pressure, proteinuria, glomerular endotheliosis, and intrauterine fetal growth restriction. At 7.5 days post-coitus, the embryos from Edn1H/+ dams, regardless of their Edn1 genotype, lagged 12 hours in development compared with embryos from WT dams, had disoriented ectoplacental cones, and retained high E-cadherin expression. In contrast, WT females mated with Edn1H/+ males, which also carried half of the fetuses with Edn1H/+ genotype, showed a mild systolic blood pressure increase only. These WT dams had 2× higher plasma soluble fms-like tyrosine kinase-1 than WT dams mated with WT males. In human first trimester trophoblast cells, pharmacological doses of ET-1 increased the cellular sFlt1 transcripts and protein secretion via both type A and B ET-1 receptors. Our data demonstrate that high maternal ET-1 production causes preeclampsia-like phenotypes during pregnancy, affecting both initial stage of trophoblast differentiation/invasion and maternal peripheral vasculature during late gestation. High fetal ET-1 production, however, could cause increased soluble fms-like tyrosine kinase-1 in the maternal circulation and contribute to blood pressure elevation.

  • blood pressure
  • coitus
  • endothelin-1
  • preeclampsia
  • vascular endothelial growth factor A
  • Received January 9, 2018.
  • Revision received January 22, 2018.
  • Accepted March 6, 2018.
  • © 2018 American Heart Association, Inc.

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    Causative Effects of Genetically Determined High Maternal/Fetal Endothelin-1 on Preeclampsia-Like Conditions in MiceNovelty and Significance
    Feng Li, Masao Kakoki, Marcela Smid, Kim Boggess, Jennifer Wilder, Sylvia Hiller, Carol Bounajim, Scott E. Parnell, Kathleen K. Sulik, Oliver Smithies and Nobuyo Maeda-Smithies
    Hypertension. 2018;71:894-903, originally published April 2, 2018
    https://doi.org/10.1161/HYPERTENSIONAHA.117.10849

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    Causative Effects of Genetically Determined High Maternal/Fetal Endothelin-1 on Preeclampsia-Like Conditions in MiceNovelty and Significance
    Feng Li, Masao Kakoki, Marcela Smid, Kim Boggess, Jennifer Wilder, Sylvia Hiller, Carol Bounajim, Scott E. Parnell, Kathleen K. Sulik, Oliver Smithies and Nobuyo Maeda-Smithies
    Hypertension. 2018;71:894-903, originally published April 2, 2018
    https://doi.org/10.1161/HYPERTENSIONAHA.117.10849
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