Methionine induced placental angiogenesis through activating WNT3A/CTNNB1-PIGF-VEGFR1 pathway

Placenta is highly susceptible to oxidative stress during pregnancy, which is a major cause of abnormal vascular development, fetal growth restriction and preterm birth. Methionine exhibits remarkable efficacy in promoting embryonic development and pregnancy outcomes, yet the role of methionine in placental antioxidant capacity and angiogenesis remains unclear.

Pregnant rats and porcine iliac artery endothelial cells (PIECs) were used in our study. Pregnant rats were fed with methionine supplementation or methionine free diet. PIECs were treated with methionine, ROS inducer, VEGFR1 inhibitor, CTNNB1 knockdown or overexpressing.

Our findings revealed that dietary methionine supplementation significantly increased the levels of glutathione, while reducing the levels of malondialdehyde in rat placentae. Moreover, experiments from PIECs treatment with ROS inducer, VEGFR1 inhibitor, knockdown or overexpressing of CTNNB1 revealed that methionine regulated angiogenesis in the placenta by modulating ROS levels and the CTNNB1 signaling pathway. Mechanistically, methionine enhanced the transsulfuration metabolism in placental vascular cells, leading to the production of the antioxidant glutathione and a reduction in ROS levels, followed by activating the WNT3A/CTNNB1 signaling pathway. CTNNB1 bind to PIGF, which promoted the phosphorylation of VEGFR1, thereby enhancing angiogenesis.

This study elucidated that methionine promoted placental angiogenesis through the ROS-WNT3A/CTNNB1-PIGF-VEGFR1 axis, providing new therapeutic targets for pregnancy complications.