OP 25 Placental differentiation and nutrient transporter expression is changed in sFlt-1 preeclampsia/IUGR mouse models

Abstract

Listen

Translate article

Introduction and objectives Impaired placental development or function leads to intrauterine growth restriction (IUGR) resulting in fetal malnutrition and deprivation of oxygen supply. Since it is known that overexpression of the human anti-angiogenic molecule sFlt-1 in mice lead to preeclampsia and intrauterine growth restriction (IUGR) in mice we established two sFlt-1 mouse models: (1) placental overexpression of human sFlt-1 by lentiviral transduced blastocysts and (2) maternal ubiquitous inducible human sFlt-1 overexpression (sFlt-1/rtTA transgenic mice). We hypothesize that sFlt-1 influence placental morphology and physiology which led to fetal IUGR. Material and methods Therefore we examined the effect of human sFlt-1 on placental morphology and physiology at embryonic day 18.5 with histologic and morphometric analyses, transcript analyses, immunoblotting, and methylation studies. Results 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, mostly the expression of placental glucose transporters, such as the glucose diffusion channel Cx26 and Glut-1 is significantly decreased. 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.