HIF1 inhibitor acriflavine rescues early-onset preeclampsia phenotype in mice lacking placental prolyl hydroxylase domain protein 2

Abstract

Preeclampsia is a serious pregnancy disorder that lacks effective treatments other than delivery.Improper sensing of oxygen changes during placentation by prolyl hydroxylases (PHD), specifically PHD2, causes placental Hypoxia-Inducible Factor-1 (HIF1) buildup and abnormal downstream signaling in early-onset preeclampsia; yet therapeutic targeting of HIF1 has never been attempted. Here we generated a conditional (placenta-specific) knockout of Phd2 in mice (Phd2 -/-cKO) to reproduce HIF1 excess and to assess anti-HIF therapy. Conditional deletion of Phd2 in the junctional zone (JZ) during pregnancy increased placental HIF1 content, resulting in abnormal placentation, impaired remodeling of the uterine spiral arteries, and fetal growth restriction. Pregnant dams developed newonset hypertension at mid-gestation (E9.5) in addition to proteinuria and renal and cardiac pathology, hallmarks of severe preeclampsia in humans. Daily injection of acriflavine, a small-molecule inhibitor of HIF1, to pregnant Phd2 -/-cKO mice from E7.5 (prior to hypertension) or E10.5 (after hypertension has been established) to E14.5 corrected placental dysmorphologies and improved fetal growth.Moreover, it reduced maternal blood pressure and reverted renal and myocardial pathology. Thus, therapeutic targeting of the HIF pathway may improve placental development and function, as well as maternal and fetal health, in preeclampsia.

Streamlined Analysis of Maternal Plasma Indicates Small Extracellular Vesicles are Significantly Elevated in Early-Onset Preeclampsia

“…Although HIF-1α signaling is essential in the early stages of pregnancy, increased oxygenation at around 10 weeks of gestation normally leads to rapid HIF-1α protein degradation in the placenta; however, persistent stabilization and elevation of placental HIF-1α protein beyond the low-oxygen intrauterine environment of the first trimester is strongly associated with the pathogenesis of EOPE [2, 22, 24-31, 63, 64, 66]. Recent animal models have further reinforced this notion: trophoblast-specific HIF-1α overexpression, as well as conditional knockout of prolyl hydroxylase domain protein 2, result in pathologic HIF-1α stabilization and consequently induce EOPE-like symptoms in mice [2,31].…”

“…HIF-1α, a transcription factor essential for embryonic and placental development as well as fetal survival, is a critical molecular mediator of oxygen sensing. HIF-1α protein is significantly elevated in placental tissues after the first trimester in EOPE pregnancies [19,22,[24][25][26][27][28][29][30][31]. EOPE placentas are reported to exhibit significantly higher levels of microRNA-210-3p (miR-210), a hypoxia-responsive micro-RNA which has been shown to form a positive signaling feedback loop with HIF-1α [32,33].…”

Hypoxia-inducible factor 1 signaling drives placental aging and can provoke preterm labor

“…Our data have implications for other adverse pregnancy outcomes beyond preterm birth, including intrauterine growth restriction and preeclampsia. Two important recent studies have examined separate mouse models with constitutively active placental HIF-1 and found that when induced from the beginning of gestation, placental HIF-1 signaling drives abnormal placentogenesis and impaired spiral artery remodeling, leading to placental hypoperfusion, fetal growth restriction, and a preeclampsia-like clinical syndrome ( Albers et al, 2019 ; Sallais et al, 2022 ). In the context of these earlier results, our study highlights the critical gestational age dependence of HIF-1 effects, having demonstrated that in a normally developed mouse placenta, induction of HIF-1 signaling during the final days of gestation leads to labor onset.…”

Hypoxia‐based critical gene biomarkers as prognostic reporters for gastric adenocarcinoma

“…Both subunits contain the basic helix–loop–helix (bHLH)‐PAS structural domain and are members of the bHLH‐Per‐ARNT‐SIM (PAS) transcription factor superfamily. Since the β subunit is structurally expressed in cells and can form dimers with the aryl hydrocarbon receptor and various other bHLH‐PAS proteins, the ɑ subunit is considered to be a specific oxygen regulatory subunit that determines the activity of HIF‐1 19–21 . Therefore, the study of establishing prognostic markers for gastric cancer survival based on hypoxia‐related molecular models has important clinical stratification implications for improving the survival of gastric cancer patients and improving their 5‐year survival rates.…”