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 6-methyladenosine(m^(6)A),the most abundant m R...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 6-methyladenosine(m^(6)A),the most abundant m RNA modification,is dysregulated in samples with preeclampsia.However,whether and how m^(6)A regulates uterine spiral artery remodeling and leads to subsequent preeclampsia in vivo remains unexplored.In this study,we generated two m^(6)A deficiency mouse models:one with a trophoblast-specific knockout of the m^(6)A methyltransferase gene Mettl3,and another with a methyltransferase enzyme mutation.Using these models,we demonstrated that m^(6)A deficiency impaired extravillous trophoblasts(EVTs)infiltration into the uterine spiral arteries,and the remodeling of the spiral arteries in vivo.We further showed that m^(6)A inhibition induced preeclampsia-like symptoms.Mechanistically,we revealed that the m^(6)A 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 m^(6)A-deficient mice.Our findings underscore the importance of m^(6)A in facilitating uterine spiral artery remodeling and prove the pathological mechanisms in vivo,suggesting a new therapeutic approach for preeclampsia caused by m^(6)A deficiency.展开更多
基金supported by the National Natural Science Foundation of China(82230053,32222016)the National Key Research and Development Program of China(2019YFA0802300,2018YFC1004100)+1 种基金the Discipline Construction Project of Guangdong Medical University(4SG23026G)the Science and Technology Program of Guangzhou,China(202201010922)。
文摘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 6-methyladenosine(m^(6)A),the most abundant m RNA modification,is dysregulated in samples with preeclampsia.However,whether and how m^(6)A regulates uterine spiral artery remodeling and leads to subsequent preeclampsia in vivo remains unexplored.In this study,we generated two m^(6)A deficiency mouse models:one with a trophoblast-specific knockout of the m^(6)A methyltransferase gene Mettl3,and another with a methyltransferase enzyme mutation.Using these models,we demonstrated that m^(6)A deficiency impaired extravillous trophoblasts(EVTs)infiltration into the uterine spiral arteries,and the remodeling of the spiral arteries in vivo.We further showed that m^(6)A inhibition induced preeclampsia-like symptoms.Mechanistically,we revealed that the m^(6)A 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 m^(6)A-deficient mice.Our findings underscore the importance of m^(6)A in facilitating uterine spiral artery remodeling and prove the pathological mechanisms in vivo,suggesting a new therapeutic approach for preeclampsia caused by m^(6)A deficiency.
