Department of Physiology and Pharmacology.
Department of Clinical Sciences, Karolinska Institutet.
J Hypertens. 2021 Aug 1;39(8):1628-1641. doi: 10.1097/HJH.0000000000002834.
Pre-eclampsia is a multisystem disorder associated with systemic vascular dysfunction and decreased nitric oxide (NO) bioactivity. Arginase competes with NO synthase (NOS) for l-arginine, and its upregulation may reduce NOS-derived NO formation or induce production of reactive oxygen species (ROS) via uncoupling of NOS, resulting in endothelial dysfunction. Red blood cells (RBCs) have emerged as key players in NO homeostasis via their interactions with the endothelium. Studies have demonstrated that abnormal RBC arginase function in patients with diabetes contributes to oxidative stress and endothelial dysfunction.
The aim of the study was to investigate if reduced NO bioavailability and increased ROS in pre-eclampsia is mediated via RBC-dependent mechanisms.
In this translational study, plasma and RBCs were isolated from gestationally matched pre-eclamptic and healthy pregnant women and co-incubated overnight with mouse aortas for vascular reactivity studies. NO bioactivity, that is, nitrate, nitrite and cGMP, was assessed in plasma. Arginase activity and expression were analysed in RBCs.
Plasma markers of NO homeostasis and signalling were decreased in pre-eclamptic women vs. healthy pregnant women. Co-incubation of aorta with pre-eclamptic RBCs, but not healthy pregnant RBCs, induced endothelial dysfunction, which was ameliorated by pharmacological inhibition of arginase, scavenging of ROS, and by nitrite treatment. This pathological vascular phenotype was not observed following incubation with pre-eclamptic plasma. Arginase expression and activity in RBCs were increased in pre-eclamptic vs. healthy pregnant women and was associated with pre-eclampsia severity. Pre-eclamptic RBC-induced endothelial dysfunction was not because of increased haemolysis/cell-free haemoglobin.
This study demonstrates a novel role of the RBC in mediating the endothelial dysfunction associated with pre-eclampsia through arginase-dependent and oxidative stress-dependent mechanisms. Targeting of RBC arginase may provide a novel treatment modality for pre-eclampsia.
子痫前期是一种多系统疾病，与全身血管功能障碍和一氧化氮（NO）生物活性降低有关。精氨酸酶与一氧化氮合酶（NOS）竞争 l-精氨酸，其上调可能通过NOS 解偶联减少 NOS 衍生的 NO 形成或诱导活性氧（ROS）的产生，从而导致内皮功能障碍。红细胞（RBC）通过与内皮细胞相互作用成为 NO 动态平衡的关键参与者。研究表明，糖尿病患者 RBC 异常精氨酸酶功能导致氧化应激和内皮功能障碍。
本研究旨在探讨子痫前期中 NO 生物利用度降低和 ROS 增加是否通过 RBC 依赖性机制介导。
在这项转化研究中，从妊娠匹配的子痫前期和健康孕妇中分离血浆和 RBC，并与小鼠主动脉共孵育过夜进行血管反应性研究。评估血浆中 NO 动态平衡和信号的生物活性，即硝酸盐、亚硝酸盐和 cGMP。分析 RBC 中的精氨酸酶活性和表达。
与健康孕妇相比，子痫前期妇女的血浆 NO 动态平衡和信号标志物降低。与健康孕妇的 RBC 共孵育不会诱导主动脉内皮功能障碍，但与子痫前期妇女的 RBC 共孵育会诱导内皮功能障碍，这种病理性血管表型可通过精氨酸酶的药理学抑制、ROS 的清除和亚硝酸盐处理得到改善。在用子痫前期血浆孵育后未观察到这种病理性血管表型。与健康孕妇相比，子痫前期妇女的 RBC 中精氨酸酶表达和活性增加，并且与子痫前期的严重程度相关。子痫前期 RBC 诱导的内皮功能障碍不是由于溶血/游离血红蛋白增加引起的。
本研究表明 RBC 通过精氨酸酶依赖性和氧化应激依赖性机制在介导与子痫前期相关的内皮功能障碍方面发挥了新的作用。靶向 RBC 精氨酸酶可能为子痫前期提供一种新的治疗方法。
