Abstract
Introduction The anti-angiogenic factor sFlt-1 is the main candidate in the progression of preeclampsia, a disease which causes placental dysfunctions often leading to IUGR. Mostly is known about the impairment of the endothelial cell function by sFlt-1, but how sFlt-1 leads to IUGR and affects the placenta and fetus is currently unknown as well as therapeutic agents against such diseases are missing. Objectives Therefore we have established two transgenic, inducible sFlt-1 mouse models: (1) maternal ubiquitous (sFlt-1/rtTA mice) and (2) placental (sFlt-1/tTA/TpbpaCre mice) overexpression of human sFlt-1. We hypothesize that sFlt-1 is involved in the development of IUGR by influencing placental development and function and is therefore a potential candidate for intervention strategies. Material and Methods We examined the effects of sFlt-1 on placental morphology and function at 18.5 dpc with morphometric and immunohistochemical analyses and transcript expression of placental marker genes, nutrient transporters and proteomic analyses. Results Ubiquitous overexpression of sFlt-1 led to IUGR of the fetuses as shown by reduced fetal weights and signs of retardation. In addition, we observed a severely impaired placental phenotype shown by enlarged maternal blood sinusoids, a reduced number of fetal vessels and an inadequate placental differentiation of the labyrinth. Glucose, fatty acid and amino acid transport seem to be negatively affected. Preliminary results of the placental overexpression of sFlt-1 revealed while expressing lower levels of sFlt-1 also IUGR. Conclusion We assume that sFlt-1 has an inhibitory effect on placental differentiation, especially on fetal vessel development. A possible reactive response could be an increase in maternal blood flow promoting dilatation of the maternal sinusoids to fulfil the nutrient requirements of the fetus. This ultimately resulted in an uteroplacental insufficiency leading to IUGR. Thus, we speculate that the alterations triggered by increased anti-angiogenesis upon sFlt-1 strongly may affect fetal outcome and programming.
Published Version
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