m6A 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. N6-methyladenosine (m6A), the most abundant mRNA modification, is dysregulated in samples with preeclampsia. However, whether and how m6A regulates uterine spiral artery remodeling and leads to subsequent preeclampsia in vivo remains unexplored. In this study, we generated two m6A deficiency mouse models: one with a trophoblast-specific knockout of the m6A methyltransferase gene Mettl3, and another with a methyltransferase enzyme mutation. Using these models, we demonstrated that m6A deficiency impaired extravillous trophoblasts (EVTs) infiltration into the uterine spiral arteries, and the remodeling of the spiral arteries in vivo. We further showed that m6A inhibition induced preeclampsia-like symptoms. Mechanistically, we revealed that the m6A 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 m6A-deficient mice. Our findings underscore the importance of m6A in facilitating uterine spiral artery remodeling and prove the pathological mechanisms in vivo, suggesting a new therapeutic approach for preeclampsia caused by m6A deficiency.