Use of HIF-2α inhibitor PT2385 in placental dysfunction: New interventions addressing fetal growth restriction and preeclampsia

Details

Supervisors

Colson, Arthur ; Depoix, Christophe

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Introduction: It is established that reduced blood flow and persistent low-oxygen tension in the placenta lead to major pregnancy complications, such as preeclampsia (PE) and fetal growth restriction (FGR). Previous work from our team have demonstrated that chronic hypoxia impairs cytotrophoblast (CTB) differentiation in vitro, involving the hypoxia-inducible factor (HIF)-2α. We hence hypothesized that HIF-2α inhibition by PT2385, an HIF-2α inhibitor, could rescue trophoblast differentiation under 2.5% O2. Materials and 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 RT-qPCR, WB, ELISA and immunofluorescence. Results: First, PT2385 efficiently inhibited HIF-2α in our model and experimental conditions. Furthermore, low-oxygen tension significantly impaired CTB differentiation compared to CTBs cultured under 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) under 2.5% O2 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) 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. Conclusion: PT2385 improved CTB differentiation and functions, as well as the angiogenic factors secretion under low-oxygen tension. These results confirm the benefits of targeting HIF-2α in placental dysfunction and highlight the use of PT2385 as a potential therapy for PE and FGR.