Specific HIF-2α (Hypoxia-Inducible Factor-2) Inhibitor PT2385 Mitigates Placental Dysfunction In Vitro and in a Rat Model of Preeclampsia (RUPP)

by Selleckchem | Jul 30 2023

Background: 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.

Methods: To evaluate its therapeutic potential, PT2385 was first studied in primary human cytotrophoblasts isolated from term placenta and exposed to 2.5% O2 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.

Results: 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.

Conclusions: 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.

Comments:

The study described aims to evaluate the potential benefits of using PT2385, an oral specific HIF-2α inhibitor, in the treatment of severe placental dysfunction associated with preeclampsia. Preeclampsia is a leading cause of maternal mortality worldwide and is characterized by insufficient remodeling of spiral arteries during early pregnancy, leading to placental dysfunction.

The researchers conducted a series of experiments to assess the therapeutic potential of PT2385. In the initial stage, they isolated primary human cytotrophoblasts from term placenta and exposed them to low oxygen levels (2.5% O2) to stabilize HIF-2α. Various assays, including viability and luciferase assays, RNA sequencing, and immunostaining, were performed to analyze the effect of PT2385 on cytotrophoblast differentiation and the balance of angiogenic factors.

The results of the in vitro experiments showed that PT2385 treatment enhanced the differentiation of cytotrophoblasts into syncytiotrophoblasts, a crucial process for normal placental function. Additionally, PT2385 treatment normalized the secretion of angiogenic factors, which are important for maintaining healthy placental blood vessels.

To assess the effects of PT2385 in vivo, the researchers used a rat model known as the selective reduced uterine perfusion pressure model, which mimics some aspects of preeclampsia. Pregnant rats were subjected to reduced blood flow to the uterus, resulting in placental dysfunction and preeclampsia-like symptoms. The researchers found that PT2385 effectively decreased the production of sFLT-1, a protein associated with preeclampsia, thereby preventing the onset of hypertension (high blood pressure) and proteinuria (presence of excess protein in the urine) in the pregnant rats.

Based on these findings, the study suggests that HIF-2α plays a role in placental dysfunction and that PT2385, as a specific HIF-2α inhibitor, has potential therapeutic benefits for treating severe preeclampsia. The results support the use of PT2385 as a potential treatment option for this condition in humans. Further research and clinical trials would be necessary to validate these findings and determine the safety and efficacy of PT2385 in human patients with severe preeclampsia.