The impact of metformin on the Bcl-2/Bax/Caspase3 signaling pathway in placental tissue of preeclampsia rats

Abstract Background: Preeclampsia (PE) is one of the leading complications affecting pregnant women globally during the perinatal period, with excessive apoptosis of trophoblast cells playing a crucial role in its pathogenesis. While Metformin (MET) has shown promise in preventing or treating PE, its mechanisms remain unclear. Objective: We sought to establish a PE rat model and evaluate MET's impact on the intrinsic (mitochondrial) apoptotic pathway (Bcl-2/Bax/Caspase3) in placental cells. We investigated whether MET could reduce excessive trophoblast cell apoptosis through this pathway, thereby improving pregnancy outcomes in PE rats. Methods: Thirty successfully impregnated Sprague-Dawley (SD) rats were randomly divided into normal saline (NS), PE, and PE+MET groups. The NS group received physiological saline injections (200mg/kg/d) from gestational day 14 to gestational day 18 (GD14-GD18). The PE and PE+MET groups received L-NAME injections (200mg/kg/d) from gestational day 14 to 18 (GD14-GD18). The PE+MET group additionally received MET via gastric gavage from GD13 to GD18. Western blot, RT-qPCR, and immunohistochemistry were employed to assess the expression of Bcl-2, Bax, and Caspase3 in placental tissues. ELISA was used to measure the expression of Bcl-2, Bax, Caspase3, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), soluble FMS-like tyrosine kinase 1 (sFlt-1), soluble endoglin (sEng), placental growth factor (PlGF), and endothelial nitric oxide synthase (eNOS) in serum. Results: MET treatment reduced blood pressure and proteinuria in PE rats and improved pregnancy outcomes. It lowered serum levels of pro-inflammatory cytokines (TNF-α, IL-6) and increased the anti-inflammatory cytokine IL-10 in PE rats. MET also restored the balance of angiogenic factors. Moreover, MET upregulated Bcl-2 expression and suppressed Bax and Caspase3 levels, suggesting its ability to suppress excessive trophoblast cell apoptosis. Conclusion: MET effectively mitigated PE in L-NAME-induced rats by lowering blood pressure, proteinuria, inflammatory damage, and trophoblast cell death while improving pregnancy outcomes and restoring the balance of angiogenic factors. This effect appears to be mediated, at least partly, by modulating the Bcl-2/Bax/Caspase3 apoptotic pathway.