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

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.

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

“…In pregnant women, the increased activity of anti-angiogenic factors induces the systemic endothelial dysfunctions and vasospasm and provokes preeclampsia [ 358 ]. MF treatment of mice with a preeclampsia-like model induced by a six-week high-fat diet (HFD) before pregnancy reduces the blood pressure, prevents the proteinuria, normalizes the fetal and maternal weight, and leads to an improvement of the placental labyrinth and fetal vascular development, impaired in the conditions of preeclampsia [ 359 ]. This is based on MF-induced normalization of placental production of MMP-2 and VEGF in preeclamptic mice, which, in turn, improves the pregnancy outcomes [ 359 ].…”

Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia

“…57 Furthermore, there is evidence that it resolves the preeclampsia phenotype in animal models. 58,59 A randomized trial by Syngelaki et al 60 examining the potential of metformin to decrease maternal and fetal weight gain in women who are obese reported a remarkable 76% reduction in rates of preeclampsia (OR, 0.24; 95% CI, 0.10e0.61; P<.001). A metaanalysis of trials assessing metformin vs insulin concluded that rates of hypertensive disorders are decreased among those administered metformin (n¼836; RR, 0.68; 95% CI, 0.48e0.95), 61 but a metaanalysis of trials where women received metformin or placebo did not find a difference in hypertensive disorders 61 (n¼609; RR, 0.86; 95% CI, 0.33e2.26; P¼.76).…”

Bioenergetics adaptations and redox homeostasis in pregnancy and related disorders

“…As previously described in section "preeclampsia", sFlt-1 and soluble endoglin are anti-angiogenic factors implicated in the pathogenesis of preeclampsia. In a model of preeclampsia in mice fed with a high-fat diet, the use of metformin has also shown to improve maternal blood pressure and foetal outcomes [125].…”