Pterostilbene promotes placental angiogenesis in pregnant sows via epigenetic regulation of the miR-369/Nrf2/HIF-1α signaling axis.

چکیده اصلی

BACKGROUND: Gestational redox imbalance impairs placental angiogenesis and function, leading to adverse pregnancy outcomes. Pterostilbene (PTE) has well-documented antioxidant and anti-inflammatory activities, yet its epigenetic regulatory mechanisms underlying placental angiogenesis, especially the microRNA-mediated pathway, remains largely elusive. OBJECTIVES: This study aimed to elucidate the mechanism by which PTE mitigates gestational oxidative stress and enhances placental vascularization in pregnant sows. METHODS: We performed in vivo experiments in a late-gestation sow model and in vitro assays in porcine placental trophoblast (pTr) cells, coupled with microRNA sequencing and molecular biological validation assays. RESULTS: Gestational oxidative stress significantly reduced placental vascular density by downregulating hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factors (VEGFA and VEGFC). MicroRNA sequencing revealed that miR-369 is the key target through which PTE in regulates placental function. Mechanistically, PTE specifically inhibited miR-369 expression, inhibited on the Nrf2/Keap1 signaling, promoted the nuclear translocation of Nrf2, and activated the endogenous antioxidant system, thereby reducing placental malondialdehyde (MDA) content by 28% and reactive oxygen species (ROS) levels by 35%. Furthermore, PTE-mediated redox homeostasis activated HIF-1α/VEGF signaling cascade, leading to a 42% increase in placental vascular density and a 51% upregulation of proliferating cell nuclear antigen (PCNA), a marker of trophoblast proliferation. CONCLUSION: This study is the first to demonstrate that PTE protects placental function via epigenetic regulation of miR-369, which coordinates the Nrf2-mediated antioxidant response and HIF-1α/VEGF-dependent angiogenesis. These findings provide a novel mechanistic basis and promising nutritional strategy for improving gestational health.

متن کامل اصلی