A Novel Role of 5-Methyl-(6S)-tetrahydrofolate in Mediating Endothelial Cell Tetrahydrobiopterin in Pregnancy and Implications for Gestational Hypertension

Background: Folate intake during pregnancy is essential for fetal development and maternal health. However, the specific effect of folic acid (FA) and 5-methyl-(6S)-tetrahydrofolate (5MTHF) on the prevention and treatment of hypertensive disorders of pregnancy remains unclear. We investigated whether FA and 5-MTHF have different effects on endothelial cell tetrahydrobiopterin (BH4) metabolism in pregnancy, and possible consequences for endothelial nitric oxide (NO) generation, maternal blood pressure (BP) and fetal growth. Methods: We analysed the maternal BP in pregnant wild-type (Gch1fl/fl) and Gch1fl/flTie2cre mice treated with either FA or 5-MTHF starting at before pregnancy, mid-pregnancy or late pregnancy. BH4, superoxide, and NO bioavailability were determined in mouse and human models of endothelial cell BH4 deficiency by HPLC. Results: In vitro studies in mouse and human endothelial cells showed that treatment with 5MTHF, but not FA, elevated BH4 levels, reduced superoxide production and increased NO synthase (NOS) activity. In primary endothelial cells isolated from women with hypertensive pregnancies, exposure to 5-MTHF, but not FA, restored the reduction in BH4 levels and NOS activity. In vivo studies in mice revealed that oral treatment with 5-MTHF, but not FA, prevented, and treated, hypertension in pregnancy, when administered either prior to or during pregnancy, respectively, and normalised placental and fetal growth restriction if administered from mid-gestation onwards. Conclusion: Collectively, these studies identify a critical role for 5-MTHF in endothelial cell function in pregnancy, related to endothelial cell BH4 availability and NOS activity. Thus, 5MTHF represents a novel therapeutic agent that may potentially improve endothelial function in hypertensive disorders of pregnancy by targeting endothelial cell BH4.