HIF1 inhibitor acriflavine rescues early-onset preeclampsia phenotype in mice lacking placental prolyl hydroxylase domain protein 2
Julien Sallais, Chanho Park, Sruthi Alahari, Tyler Porter, Ruizhe Liu, Merve Kurt, Abby Farrell, Martin Post, Isabella Caniggia
Julien Sallais, Chanho Park, Sruthi Alahari, Tyler Porter, Ruizhe Liu, Merve Kurt, Abby Farrell, Martin Post, Isabella Caniggia
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Research Article Development Reproductive biology

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 (PHDs), 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 during pregnancy increased placental HIF1 content, resulting in abnormal placentation, impaired remodeling of the uterine spiral arteries, and fetal growth restriction. Pregnant dams developed new-onset hypertension at midgestation (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 had 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.

Authors

Julien Sallais, Chanho Park, Sruthi Alahari, Tyler Porter, Ruizhe Liu, Merve Kurt, Abby Farrell, Martin Post, Isabella Caniggia

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Figure 6

Placental removal of Phd2 leads to maternal heart alterations.

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Placental removal of Phd2 leads to maternal heart alterations. (A) Repre...
(A) Representative H&E staining of sagittal maternal heart sections at day 17.5 of pregnancy from WT and Phd2–/– cKO pregnant mice (scale bars represent 1,000 μm). (B) Morphometric assessment of cardiomyocyte diameter in heart sections from WT and Phd2–/– cKO mice at day 17.5 of pregnancy (*P < 0.05; unpaired Student’s t test; mean of 3 H&E images from LV wall per mouse; n = 3 WT and n = 3 Phd2–/– cKO dams, respectively; scale bars represent 20 μm). (C) Representative WBs for PHD2 and associated densitometry in whole heart lysates from WT and Phd2–/– cKO dams. Data are expressed as fold change relative to ACTB (no significant difference relative to WT, n = 3 WT and n = 4 Phd2–/– cKO placentae; PHD2 and ACTB lanes were run on the same gel but were noncontiguous). (D) Representative TEM images of maternal heart muscle at day 17.5 of gestation of WT, Phd2–/– cKO and Phd2–/– cKO mice injected with ACF during early pregnancy (GD7.5–14.5; top panel: scale bars represent 2 μm; bottom panel: scale bars represent 1 μm). White stars indicate fragmented mitochondria. M, mitochondria; S, sarcomere. (E) Mitochondrial morphometric analysis of cardiomyocytes at day 17.5 of gestation of WT, Phd2–/– cKO, and Phd2–/– cKO mice injected with ACF during early (GD7.5–14.5) pregnancy “(*P < 0.05, ***P < 0.001, ****P < 0.0001 relative to mitochondria of WT pregnant mice, 1-way ANOVA, Newman-Keuls post hoc test; minimum of 4 images per section; n = 3 separate pregnant mice per condition).