Causative Effects of Genetically Determined High Maternal/Fetal Endothelin-1 on Preeclampsia-Like Conditions in Mice. Issue 5 (May 2018)

• Record Type: Journal Article
• Authors: Li, Feng; Kakoki, Masao; Smid, Marcela; Boggess, Kim; Wilder, Jennifer; Hiller, Sylvia; Bounajim, Carol; Parnell, Scott E.; Sulik, Kathleen K.; Smithies, Oliver; Maeda-Smithies, Nobuyo
• Is Part Of: Hypertension. Volume 71:Issue 5(2018:May)
• Publication Date: 2018-05
• Subjects: blood pressure -- coitus -- endothelin-1 -- preeclampsia -- vascular endothelial growth factor A; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.117.10849
• Languages: English
• ISSNs: 0194-911X

Abstract

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 Edn1 H/ + 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 Edn1 H/ + 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 Edn1 H/ + males, which also carried half of the fetuses with Edn1 H/ + 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. Abstract : Supplemental Digital Content is available in the text.