Effect of Metformin on a Preeclampsia-Like Mouse Model Induced by High-Fat Diet

Fuchuan Wang, Guangming Cao, Wei Yi, Li Li, Xiuzhen Cao, Fuchuan Wang, Guangming Cao, Wei Yi, Li Li, Xiuzhen Cao

Abstract

Background: Metformin has been reported to decrease insulin resistance and is associated with a lower risk of pregnancy-induced hypertension and preeclampsia. It is widely accepted that the placenta plays a crucial role in the development of preeclampsia. Our aim is to explore the effect of metformin on preeclampsia.

Study design: We examined control diet-fed (isocaloric diet) pregnant mice (CTRL group), pregnant mice fed a high-fat diet (HF group), and high-fat-diet-fed pregnant mice treated with metformin (HF-M group). The HF mice were fed a high-fat diet six weeks before pregnancy to establish a preeclampsia-like model; then, the group was randomly divided into a HF group and a HF-M group after pregnancy. Blood pressure, urine protein, pregnancy outcomes, protein expression, and histopathological changes in the placentas of all groups were examined and statistically analysed.

Results: We observed that metformin significantly improved high blood pressure, proteinuria, and foetal and placental weights in the HF-M group compared with the HF group. Metformin significantly improved placental labyrinth and foetal vascular development in preeclampsia. In addition, metformin effectively increased matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) levels in the placenta.

Conclusions: Our results suggest that metformin can improve preeclamptic symptoms and pregnancy outcomes.

Conflict of interest statement

The authors declare that there are no conflicts of interest regarding the publication of this article.

Copyright © 2019 Fuchuan Wang et al.

Figures

Figure 1
Figure 1
Effects of treatment with metformin on maternal signs of preeclampsia. (a) Systolic blood pressure. (b) Diastolic blood pressure. (c) Mean arterial blood pressure. (d) Urinary protein. The results are presented in mean ± SD. ∗P < 0.05.
Figure 2
Figure 2
The weights of (a) the pregnant mice, (b) the placenta, and (c) the foetus at day 18.5 of pregnancy. Data are expressed as the mean ± SD. ∗P < 0.05 between two groups.
Figure 3
Figure 3
Analysis of placental structure. (a) Placental HE staining results of the three groups. The magnification is 20x in the upper panels. (b–d) Bar charts show the labyrinth and sponge of the placenta. (e) An immunohistochemical analysis of laminin in the placenta. The magnification is 400x in the panels. Pseudocolour is used to indicate foetal blood vessels (red) and the maternal blood sinusoid (blue) in the placental labyrinth. (f–g) Bar graphs show the quantitative results of the red and blue areas of all placentas in each group, indicating the area of the maternal blood sinusoid (MBS) and foetal blood vessels (FBV). The statistical analysis was based on the results of all placentas in each group. Data are expressed as the mean ± SD. ∗P < 0.05 between two groups.
Figure 4
Figure 4
The protein expression of the placenta by western blotting. (a) Western blotting shows the relative expression of VEGF and MMP-2 in the placentas. (b-c) Bar graphs show the relative protein levels of VEGF and MMP-2 based on the statistical analysis of the western blotting results. Data are expressed as the mean ± SD. ∗P < 0.05 between two groups.

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