Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique (A.C., C.L.D., I.L., C.L., M.P.d.N., K.B., C.H., F.D.), Université catholique de Louvain, Brussels, Belgium.
Pôle de Recherche en Pharmacothérapie, Institut de Recherche Expérimentale et Clinique (A.C., M.B., P.S.), Université catholique de Louvain, Brussels, Belgium.
Hypertension. 2023 May;80(5):1011-1023. doi: 10.1161/HYPERTENSIONAHA.122.20739. Epub 2023 Mar 6.
Preeclampsia is one of the leading causes of maternal mortality worldwide and is strongly associated with long-term morbidity in mothers and newborns. Referred to as one of the deep placentation disorders, insufficient remodeling of the spiral arteries during the first trimester remains a major cause of placental dysfunction. Persisting pulsatile uterine blood flow causes abnormal ischemia/reoxygenation phenomenon in the placenta and stabilizes the HIF-2α (hypoxia-inducible factor-2α) in the cytotrophoblasts. HIF-2α signaling impairs trophoblast differentiation and increases sFLT-1 (soluble fms-like tyrosine kinase-1) secretion, which reduces fetal growth and causes maternal symptoms. This study aims to evaluate the benefits of using PT2385-an oral specific HIF-2α inhibitor-to treat severe placental dysfunction.
To evaluate its therapeutic potential, PT2385 was first studied in primary human cytotrophoblasts isolated from term placenta and exposed to 2.5% O to stabilize HIF-2α. Viability and luciferase assays, RNA sequencing, and immunostaining were used to analyze differentiation and angiogenic factor balance. The ability of PT2385 to mitigate maternal manifestations of preeclampsia was studied in the selective reduced uterine perfusion pressure model performed in Sprague-Dawley rats.
In vitro, RNA sequencing analysis and conventional techniques showed that treated cytotrophoblast displayed an enhanced differentiation into syncytiotrophoblasts and normalized angiogenic factor secretion compared with vehicle-treated cells. In the selective reduced uterine perfusion pressure model, PT2385 efficiently decreased sFLT-1 production, thus preventing the onset of hypertension and proteinuria in pregnant dams.
These results highlight HIF-2α as a new player in our understanding of placental dysfunction and support the use of PT2385 to treat severe preeclampsia in humans.
子痫前期是全球孕产妇死亡的主要原因之一，与母婴长期发病密切相关。它被称为深层胎盘病之一，在妊娠早期螺旋动脉重塑不足仍然是胎盘功能障碍的主要原因。持续的脉动性子宫血流导致胎盘异常缺血/再氧合现象，并使绒毛外滋养细胞中的 HIF-2α（缺氧诱导因子-2α）稳定。HIF-2α 信号通路会损害滋养细胞分化并增加 sFLT-1（可溶性 fms 样酪氨酸激酶-1）的分泌，从而减少胎儿生长并导致母体出现症状。本研究旨在评估使用 PT2385（一种口服特异性 HIF-2α 抑制剂）治疗严重胎盘功能障碍的益处。
为了评估其治疗潜力，首先在从足月胎盘分离的原代人绒毛外滋养细胞中研究了 PT2385，使其在 2.5%O 下稳定 HIF-2α。使用活力和荧光素酶测定、RNA 测序和免疫染色来分析分化和血管生成因子平衡。在选择性减少子宫灌注压模型中研究了 PT2385 减轻子痫前期母体表现的能力，该模型在 Sprague-Dawley 大鼠中进行。
在体外，RNA 测序分析和常规技术表明，与载体处理的细胞相比，处理后的绒毛外滋养细胞显示出增强的向合体滋养细胞的分化，并使血管生成因子的分泌正常化。在选择性减少子宫灌注压模型中，PT2385 有效地降低了 sFLT-1 的产生，从而防止了妊娠母体高血压和蛋白尿的发生。
这些结果强调了 HIF-2α 在我们对胎盘功能障碍的理解中的新作用，并支持使用 PT2385 治疗人类严重子痫前期。
