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.

Murine transcription factor Math6 is a regulator of placenta development

“…Indeed, it is known that other/further bHLH transcription factors like Mash2 and Hand1 regulate trophoblast proliferation and differentiation and therefore might compensate an endogenous lack of Math6 44 , 45 . In agreement with this assumption we found a regular expression of Hand1 and of Tpbpa, which is expressed by spongiotrophoblast and glycogen trophoblasts in the junctional zone 46 .…”

Down-Regulation of Laminin (LN)- α5 is Associated with Preeclampsia and Impairs Trophoblast Cell Viability and Invasiveness Through PI3K Signaling Pathway

“…DNA methylation is essential for normal development of extraembryonic tissues, particularly the invasive behavior of trophoblast cells [37]. The placenta is unique in that it is hypomethylated compared to somatic tissues [38], and some genes such as DNA methyltransferase 3A, DNA methyltransferase 1, and the human anti-angiogenic molecule sFlt-1 are hypomethylated in the placenta [39][40][41]. This suggests that there are global changes in DNA methylation in the placenta throughout pregnancy, contributing to differential gene expression across gestation.…”

Regulation of Placental Development and Its Impact on Fetal Growth—New Insights From Mouse Models

“…Embryos overexpressing human sFlt1 , which as mentioned earlier is implicated in early-onset pre-eclampsia with IUGR, develop a small labyrinth with reduced expression of the glucose diffusion channel Connexin26 ( Cx26 ). In contrast to their decreased expression of Cx26, sFlt1 overexpressing embryos increase fatty acid and cholesterol transport by upregulation of Cd36 and Abca1 expression, respectively ( 104 ). Similarly, mice subjected to dietary restriction during pregnancy increase system A amino acid transporter activity leading to increased fetal amino acid accumulation ( 39 ).…”