BACKGROUND Folate intake during pregnancy is essential for fetal development and maternal health. However, the specific effects of folic acid (FA) and 5-methyl-(6S)-tetrahydrofolate (5-MTHF) on the prevention and treatment of hypertensive disorders of pregnancy remain unclear. We investigated whether FA and 5-MTHF have different effects on endothelial cell tetrahydrobiopterin (BH4) metabolism in pregnancy and the possible consequences for endothelial NO generation, maternal blood pressure, and fetal growth. METHODS We analyzed the maternal blood pressure in pregnant wild-type (Gch1fl/fl) and Gch1fl/fl Tie2cre mice treated with either FA or 5-MTHF starting 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 high-performance liquid chromatography. RESULTS In vitro studies in mouse and human endothelial cells showed that treatment with 5-MTHF, but not FA, elevated BH4 levels, reduced superoxide production, and increased NO synthase 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 NO synthase 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 before or during pregnancy, respectively, and normalized placental and fetal growth restriction if administered from mid-gestation onward. CONCLUSIONS Collectively, these studies identify a critical role for 5-MTHF in endothelial cell function in pregnancy, related to endothelial cell BH4 availability and NO synthase activity. Thus, 5-MTHF represents a novel therapeutic agent that may potentially improve endothelial function in hypertensive disorders of pregnancy by targeting endothelial cell BH4.

中文翻译：

---

5-甲基-(6S)-四氢叶酸在妊娠中介导内皮细胞四氢生物蝶呤中的新作用及其对妊娠高血压的影响。


背景技术怀孕期间叶酸的摄入对于胎儿发育和孕产妇健康至关重要。然而，叶酸（FA）和5-甲基-（6S）-四氢叶酸（5-MTHF）对预防和治疗妊娠期高血压疾病的具体作用仍不清楚。我们研究了 FA 和 5-MTHF 对妊娠期内皮细胞四氢生物蝶呤 (BH4) 代谢是否有不同的影响，以及对内皮 NO 生成、母体血压和胎儿生长可能产生的影响。方法 我们分析了从怀孕前、怀孕中期或怀孕晚期开始接受 FA 或 5-MTHF 治疗的怀孕野生型 (Gch1fl/fl) 和 Gch1fl/fl Tie2cre 小鼠的母体血压。通过高效液相色谱法测定内皮细胞 BH4 缺乏的小鼠和人类模型中的 BH4、超氧化物和 NO 生物利用度。结果 小鼠和人内皮细胞的体外研究表明，用 5-MTHF（而非 FA）处理可提高 BH4 水平，减少超氧化物产生，并增加 NO 合酶活性。在从患有高血压妊娠的女性中分离出的原代内皮细胞中，暴露于 5-MTHF 而不是 FA 可以恢复 BH4 水平和 NO 合酶活性的降低。小鼠体内研究表明，在怀孕前或怀孕期间口服 5-MTHF（而非 FA）口服治疗可以预防和治疗妊娠期高血压，如果从妊娠中期开始服用，可以使胎盘和胎儿生长受限正常化。结论 总的来说，这些研究确定了 5-MTHF 在妊娠期内皮细胞功能中的关键作用，与内皮细胞 BH4 可用性和 NO 合酶活性相关。 因此，5-MTHF 代表了一种新型治疗剂，可能通过靶向内皮细胞 BH4 来改善妊娠期高血压疾病的内皮功能。