title: Placental-Specific Overexpression of sFlt-1 Alters Trophoblast Differentiation and Nutrient Transporter Expression in an IUGR Mouse Model.
abstract: Since it is known that placental overexpression of the human anti-angiogenic molecule sFlt-1, the main candidate in the progression of preeclampsia, lead to intrauterine growth restriction (IUGR) in mice by lentiviral transduction of mouse blastocysts, we hypothesize that sFlt-1 influence placental morphology and physiology resulting in fetal IUGR. We therefore examined the effect of sFlt-1 on placental morphology and physiology at embryonic day 18.5 with histologic and morphometric analyses, transcript analyses, immunoblotting, and methylation studies. Interestingly, placental overexpression of sFlt-1 leads to IUGR in the fetus and results in lower placental weights. Moreover, we observed altered trophoblast differentiation with reduced expression of IGF2, resulting in a smaller placenta, a smaller labyrinth, and the loss of glycogen cells in the junctional zone. Changes in IGF2 are accompanied by small changes in its DNA methylation, whereas overall DNA methylation is unaffected. In addition, the expression of placental nutrient transporters, such as the glucose diffusion channel Cx26, is decreased. In contrast, the expression of the fatty acid transporter CD36 and the cholesterol transporter ABCA1 is significantly increased. In conclusion, placental sFlt-1 overexpression resulted in a reduction in the differentiation of the spongiotrophoblast into glycogen cells. These findings of a reduced exchange area of the labyrinth and glycogen stores, as well as decreased expression of glucose transporter, could contribute to the intrauterine growth restriction phenotype. All of these factors change the intrauterine availability of nutrients. Thus, we speculate that the alterations triggered by increased anti-angiogenesis strongly affect fetal outcome and programming. J. Cell. Biochem. 118: 1316-1329, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kühnel
authors.affiliation: Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Kleff
authors.affiliation: Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Violeta
authors.initials: V
authors.lastname: Stojanovska
authors.affiliation: Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kaiser
authors.affiliation: Central Animal Laboratory, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Waldschütz
authors.affiliation: Experimental and Clinical Research Center, a joint cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany.|Berlin Institute of Health (BIH), Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Herse
authors.affiliation: Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Torsten
authors.initials: T
authors.lastname: Plösch
authors.affiliation: Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Winterhager
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gellhaus
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000473:pathology; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010920:Placenta / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018955:CD36 Antigens; D000072259:Connexin 26; D017630:Connexins; D006003:Glycogen; D007335:Insulin-Like Growth Factor II; D040281:Vascular Endothelial Growth Factor Receptor-1; C577833:Abca1 protein, mouse; C000607043:Gjb2 protein, mouse; C513121:IGF2 protein, mouse; C501162:FLT1 protein, human
keywords: DIFFERENTIATION; HUMAN sFlt-1; INTRAUTERINE GROWTH RESTRICTION; MOUSE PLACENTA; MOUSE TROPHOBLAST; NUTRIENT TRANSPORTER