Use of the Hypoxia-Inducible Factor (HIF)-2α Inhibitor PT2385 in Placental Dysfunction: New Intervention Addressing Fetal Growth Restriction and Preeclampsia

Colson, Arthur;Lambert, Isaline;Depoix, Christophe;Hubinont, Corinne;Debiève, Frédéric;et.al.
(2021) 68th annual meeting of the Society for Reproductive Investigation — Location: Boston (6.July.2021)

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INTRODUCTION It is well established that insufficient remodeling of the uterine arteries could lead to a persistent low-oxygen environment in the placenta. Thus, chronic hypoxia persisting after the first trimester of pregnancy is thought to participate in the development of pre-eclampsia (PE) and/or fetal growth restriction (FGR). Our previous work demonstrated that low-oxygen tension impairs placental function and development through HIF-2α signaling. Here, we studied the effects of a new, selective, and orally available HIF-2α inhibitor – PT2385 – on primary human cytotrophoblast (CTB) differentiation in vitro. OBJECTIVE To study the effects of PT2385 on CTB differentiation and functions under 2.5% O2. METHODS Primary human CTBs isolated from normal term placentas (N = 3, n = 6) were cultivated under low-oxygen condition (2.5% O2) and exposed to increasing concentrations of PT2385 for 96 hours. The effects of the drug on CTB differentiation and functions were evaluated by RNA sequencing, RT-qPCR, western blot, ELISA, and immunofluorescence. Statistical analyses included ANOVA one-way and Student’s t-test and a P <.05 was considered statistically significant. RESULTS We first controlled that PT2385 efficiently inhibited HIF-2α in our model of CTBs differentiation under 2.5% O2. As expected, low-oxygen tension significantly impaired CTB differentiation compared to 21% O2. However, increasing concentrations of PT2385 radically improved CGB gene expression (4.20-fold increase, P = 0.0037) and hCG secretion (2.57-fold increase, P = 0.0095) in comparison with vehicle-treated cells. In addition, PT2385 increased the expression of the two syncytialization markers GCM1 (2.45-fold increase, P <0.0001) and syncytin-1 (1.81-fold increase; P = 0.0007) compared to vehicle-treated cells. PT2385 also improved the fusion index (2.15-fold increase, P = 0.0002). Finally, PT2385 increased placental growth factor (PGF) gene expression (2.71-fold increase, P = 0.0008) and protein secretion (4.15-fold increase, P = 0.0040) by activating the promoter while decreasing soluble fms-like tyrosine kinase-1 (sFLT-1) secretion in comparison with vehicle-treated cells (2.66-fold decrease, P = 0.0499), thus significantly inverting the angiogenic balance. The differential gene expression analysis confirmed that PT2385 enhanced the CTB differentiation into syncytiotrophoblast. Interestingly, the gene set enrichment analysis revealed that the ovarian steroidogenesis and the mTOR signaling pathway sets (KEGG) as well as the placental development set (GO) were all significantly enriched by the treatment. CONCLUSION PT2385 improved CTB differentiation and functions, as well as the angiogenic factors secretion under low-oxygen tension. These results confirm the benefit of targeting HIF-2α in placental dysfunction and highlight the use of PT2385 as a potential therapy for PE and FGR.
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Colson, A., Lambert, I., Depoix, C., Hubinont, C., Sonveaux, P., & Debiève, F. (2021). Use of the Hypoxia-Inducible Factor (HIF)-2α Inhibitor PT2385 in Placental Dysfunction: New Intervention Addressing Fetal Growth Restriction and Preeclampsia. 68th annual meeting of the Society for Reproductive Investigation, Boston. https://hdl.handle.net/2078.5/234053