Jin Meiyuan, Cao Bin, Lin Chao, Li Jiayong, Xu Qiang, Ren Qianlei, Xu Shouying, Tang Chao
National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Obstetrics, Tongde Hospital of Zhejiang Province, Hangzhou, China.
Front Pharmacol. 2022 Mar 21;13:849074. doi: 10.3389/fphar.2022.849074. eCollection 2022.
Preeclampsia (PE), a pregnancy-specific syndrome with the major molecular determinants of placenta-borne oxidative stress and consequently impaired nitric oxide (NO) generation, has been considered to be one of the leading causes of maternal morbidity as well as mortality and preterm delivery worldwide. Several medical conditions have been found to be associated with increased PE risk, however, the treatment of PE remains unclear. Here, we report that Tianma Gouteng Decoction (TGD), which is used clinically for hypertension treatment, regulates oxidative stress and NO production in human extravillous trophoblast-derived TEV-1 cells. In human preeclamptic placental explants, reactive oxygen species (ROS) levels were elevated and NO production was inhibited, while TGD treatment at different periods effectively down-regulated the HO-induced ROS levels and significantly up-regulated the HO-suppressed NO production in human TEV-1 cells. Mechanistically, TGD enhanced the activity of total nitric oxide synthase (TNOS), which catalyze L-arginine oxidation into NO, and simultaneously, TGD promoted the expression of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS), two isoforms of nitric oxide synthetases (NOS) in human placenta, resulting in the increased NO generation. More importantly, TGD administration not only increased the weight gain during pregnancy and revealed a hypotensive effect, but also improved the placental weight gain and attenuated fetal growth restriction in an NG-nitro-L-arginine methyl ester (L-NAME)-induced mouse PE-like model. Our results thereby provide new insights into the role of TGD as a potentially novel treatment for PE.
子痫前期（PE）是一种妊娠特异性综合征，其主要分子决定因素是胎盘源性氧化应激，进而导致一氧化氮（NO）生成受损，被认为是全球孕产妇发病、死亡及早产的主要原因之一。已发现多种医学状况与PE风险增加有关，然而，PE的治疗方法仍不明确。在此，我们报告临床用于治疗高血压的天麻钩藤饮（TGD）可调节人绒毛外滋养层来源的TEV-1细胞中的氧化应激和NO生成。在人子痫前期胎盘外植体中，活性氧（ROS）水平升高且NO生成受到抑制，而不同时期的TGD处理可有效下调人TEV-1细胞中HO诱导的ROS水平，并显著上调HO抑制的NO生成。机制上，TGD增强了总一氧化氮合酶（TNOS）的活性，该酶催化L-精氨酸氧化为NO，同时，TGD促进了人胎盘中两种一氧化氮合酶（NOS）同工型，即神经元型一氧化氮合酶（nNOS）和内皮型一氧化氮合酶（eNOS）的表达，从而导致NO生成增加。更重要的是，在NG-硝基-L-精氨酸甲酯（L-NAME）诱导的小鼠PE样模型中，给予TGD不仅增加了孕期体重增加并显示出降压作用，还改善了胎盘重量增加并减轻了胎儿生长受限。因此，我们的结果为TGD作为PE潜在新疗法的作用提供了新的见解。
