Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
Vascul Pharmacol. 2023 Jun;150:107168. doi: 10.1016/j.vph.2023.107168. Epub 2023 Mar 24.
Pregnancy-associated vascular remodelling is essential for both maternal and fetal health. We have previously shown that maternal endothelial cell tetrahydrobiopterin (BH4) deficiency causes poor pregnancy outcomes. Here, we investigated the role and mechanisms of endothelial cell-mediated vasorelaxation function in these outcomes.
The vascular reactivity of mouse aortas and uterine arteries from non-pregnant and pregnant endothelial cell-specific BH4 deficient mice (Gch1Tie2cre mice) was assessed by wire myography. Systolic blood pressure was assessed by tail cuff plethysmography.
In late pregnancy, systolic blood pressure was significantly higher (∼24 mmHg) in Gch1Tie2cre mice compared with wild-type littermates. This was accompanied by enhanced vasoconstriction and reduced endothelial-dependent vasodilation in both aorta and uterine arteries from pregnant Gch1Tie2cre mice. In uterine arteries loss of eNOS-derived vasodilators was partially compensated by upregulation of intermediate and large-conductance Ca-activated K channels. In rescue experiments, oral BH4 supplementation alone did not rescue vascular dysfunction and pregnancy-induced hypertension in Gch1Tie2cre mice. However, combination with the fully reduced folate, 5-methyltetrahydrofolate (5-MTHF), restored endothelial cell vasodilator function and blood pressure.
We identify a critical requirement for maternal endothelial cell Gch1/BH4 biosynthesis in endothelial cell vasodilator function in pregnancy. Targeting vascular Gch1 and BH4 biosynthesis with reduced folates may provide a novel therapeutic target for the prevention and treatment of pregnancy-related hypertension.
妊娠相关的血管重塑对母婴健康都至关重要。我们先前的研究表明，母体血管内皮细胞四氢生物蝶呤（BH4）缺乏会导致妊娠结局不良。在此，我们研究了内皮细胞介导的血管舒张功能在这些结果中的作用和机制。
通过线描法评估非妊娠和妊娠内皮细胞特异性 BH4 缺乏小鼠（Gch1Tie2cre 小鼠）的小鼠主动脉和子宫动脉的血管反应性。通过尾套容积描记法评估收缩压。
在妊娠晚期，Gch1Tie2cre 小鼠的收缩压明显高于野生型同窝仔鼠（约 24mmHg）。这伴随着妊娠 Gch1Tie2cre 小鼠的主动脉和子宫动脉的血管收缩增强和内皮依赖性血管舒张减少。在子宫动脉中，eNOS 衍生的血管舒张剂的损失部分由中大和大电导钙激活的 K 通道的上调所补偿。在挽救实验中，单独口服 BH4 补充剂不能挽救 Gch1Tie2cre 小鼠的血管功能障碍和妊娠引起的高血压。然而，与完全还原的叶酸（5-甲基四氢叶酸，5-MTHF）联合使用恢复了内皮细胞血管舒张功能和血压。
我们确定了母体血管内皮细胞 Gch1/BH4 生物合成在妊娠内皮细胞血管舒张功能中的关键要求。用还原叶酸靶向血管 Gch1 和 BH4 生物合成可能为预防和治疗妊娠相关高血压提供一个新的治疗靶点。
