mA deficiency impairs uterine spiral artery remodeling to induce preeclampsia-like symptoms via FGF2.

Failures in uterine spiral artery remodeling can lead to placental defects and subsequent preeclampsia, a leading cause of fetal and maternal mortality during pregnancy. N-methyladenosine (mA), the most abundant mRNA modification, is dysregulated in samples with preeclampsia. However, whether and how mA regulates uterine spiral artery remodeling and leads to subsequent preeclampsia in vivo remains unexplored. In this study, we generated two mA deficiency mouse models: one with a trophoblast-specific knockout of the mA methyltransferase gene Mettl3, and another with a methyltransferase enzyme mutation. Using these models, we demonstrated that mA deficiency impaired extravillous trophoblasts (EVTs) infiltration into the uterine spiral arteries, and the remodeling of the spiral arteries in vivo. We further showed that mA inhibition induced preeclampsia-like symptoms. Mechanistically, we revealed that the mA modification of FGF2 mRNA, which encodes a secreted peptide implicated in preeclampsia, facilitated its expression. Notably, administration of the FGF2 peptide largely restored EVTs invasion and uterine spiral artery remodeling in mA-deficient mice. Our findings underscore the importance of mA in facilitating uterine spiral artery remodeling and prove the pathological mechanisms in vivo, suggesting a new therapeutic approach for preeclampsia caused by mA deficiency.