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

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.