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

Autor: Colson A; 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.; Department of Obstetrics (A.C., K.B., C.H., F.D.), Cliniques universitaires Saint-Luc, Brussels, Belgium., Depoix CL; 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., Lambert I; 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., Leducq C; 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., Bedin M; Pôle de Recherche en Pharmacothérapie, Institut de Recherche Expérimentale et Clinique (A.C., M.B., P.S.), Université catholique de Louvain, Brussels, Belgium., De Beukelaer M; Imaging Core Facility 2IP, Institut de Recherche Expérimentale et Clinique (M.D.B.), Université catholique de Louvain, Brussels, Belgium., Gatto L; Unit of Computational Biology and Bioinformatics, de Duve Institute (L.G., A.L.), Université catholique de Louvain, Brussels, Belgium., Loriot A; Unit of Computational Biology and Bioinformatics, de Duve Institute (L.G., A.L.), Université catholique de Louvain, Brussels, Belgium., Peers de Nieuwburgh M; 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., Bouhna K; 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.; Department of Obstetrics (A.C., K.B., C.H., F.D.), Cliniques universitaires Saint-Luc, Brussels, Belgium., Baldin P; Department of Pathology (P.B.), Cliniques universitaires Saint-Luc, Brussels, Belgium., Hubinont C; 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.; Department of Obstetrics (A.C., K.B., C.H., F.D.), Cliniques universitaires Saint-Luc, Brussels, Belgium., Sonveaux P; Pôle de Recherche en Pharmacothérapie, Institut de Recherche Expérimentale et Clinique (A.C., M.B., P.S.), Université catholique de Louvain, Brussels, Belgium.; Walloon Excellence in Life Sciences and Biotechnology Research Institute, Wavre, Belgium (P.S.)., Debiève F; 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.; Department of Obstetrics (A.C., K.B., C.H., F.D.), Cliniques universitaires Saint-Luc, Brussels, Belgium.
Jazyk: angličtina
Zdroj: Hypertension (Dallas, Tex. : 1979) [Hypertension] 2023 May; Vol. 80 (5), pp. 1011-1023. Date of Electronic Publication: 2023 Mar 06.
DOI: 10.1161/HYPERTENSIONAHA.122.20739
Abstrakt: 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% O 2 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.
Databáze: MEDLINE
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