Supplemental Digital Content is available in the text. Increasing evidence suggests a role for the ET (endothelin) system in preeclampsia. Hence, blocking this system with endothelin receptor antagonists (ERAs) could be a therapeutic strategy. Yet, clinical studies are lacking due to possible teratogenic effects of ERAs. In this study, we investigated the placental transfer of ERAs and their effect on ET-1-mediated vasoconstriction. Term placentas were dually perfused with the selective ETAR (ET type A receptor) antagonists sitaxentan and ambrisentan or the nonselective ETAR/ETBR antagonist macitentan and subsequently exposed to ET-1 in the fetal circulation. ET-1 concentration-response curves after incubation with sitaxentan, ambrisentan, macitentan, or the selective ETBR antagonist BQ-788 were also constructed in isolated chorionic plate arteries using wire-myography, and gene expression of the ET-system was quantified in healthy and early onset preeclamptic placentas. At steady state, the mean fetal-to-maternal transfer ratios were 0.32±0.05 for sitaxentan, 0.21±0.02 for ambrisentan, and 0.05±0.01 for macitentan. Except for BQ-788, all ERAs lowered the response to ET-1, both in the perfused cotyledon and isolated chorionic plate arteries. Placental gene expression of ECE-1, ETAR, and ETBR were comparable in healthy and preeclamptic placentas, while ET-1 expression was higher in preeclampsia. Our study is the first to show direct transfer of ERAs across the term human placenta. Furthermore, ETAR exclusively mediates ET-1-induced constriction in the fetoplacental vasculature. Given its limited transfer, macitentan could be considered as potential preeclampsia therapy. Extending knowledge on placental transfer to placentas of preeclamptic pregnancies is required to determine whether ERAs might be applied safely in preeclampsia.

中文翻译：

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内皮素受体拮抗剂在人胎盘中的转移和血管作用

补充数字内容在文本中可用。越来越多的证据表明 ET（内皮素）系统在先兆子痫中的作用。因此，用内皮素受体拮抗剂 (ERA) 阻断该系统可能是一种治疗策略。然而，由于 ERAs 可能的致畸作用，缺乏临床研究。在这项研究中，我们调查了 ERAs 的胎盘转移及其对 ET-1 介导的血管收缩的影响。足月胎盘用选择性 ETAR（ET A 型受体）拮抗剂西他生坦和安立生坦或非选择性 ETAR/ETBR 拮抗剂 macitentan 进行双重灌注，随后在胎儿循环中暴露于 ET-1。与西他生坦、安立生坦、马西替坦一起孵育后的 ET-1 浓度-反应曲线，或选择性 ETBR 拮抗剂 BQ-788 也在分离的绒毛膜板动脉中构建，使用线肌描记术，并且在健康和早发性先兆子痫胎盘中量化 ET 系统的基因表达。在稳态时，西他生坦的平均胎母转移比为 0.32±0.05，安立生坦为 0.21±0.02，马西替坦为 0.05±0.01。除了 BQ-788，所有 ERA 都降低了对 ET-1 的反应，在灌注的子叶和分离的绒毛膜板动脉中。ECE-1、ETAR 和 ETBR 的胎盘基因表达在健康胎盘和先兆子痫胎盘中相当，而 ET-1 在先兆子痫中的表达更高。我们的研究首次显示 ERAs 在人类胎盘中的直接转移。此外，ETAR 专门介导 ET-1 诱导的胎儿胎盘血管收缩。鉴于其有限的转移，macitentan 可被视为潜在的先兆子痫治疗。需要扩展有关先兆子痫妊娠的胎盘转移的知识，以确定 ERAs 是否可以安全地应用于先兆子痫。