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 4

Loss of Phd2 in JZ layer results in fetal growth restriction and elevated maternal blood pressure.

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Loss of Phd2 in JZ layer results in fetal growth restriction and elevate...
(A) Average weight of embryos from WT and Phd2–/– cKO pregnant mothers immediately after sacrifice at gestational day 14.5 (*P < 0.05 relative to the WT, unpaired Student’s t test; n = 4 WT litters, 38 embryos, and n = 4 Phd2–/– cKO litters, 37 embryos) and gestational day 17.5 (*P < 0.05 relative to the WT, unpaired Student’s t test; n = 6 WT litters, 71 embryos, and n = 5 Phd2–/– cKO litters, 52 embryos). (B) Representative gross morphology of placentae and embryos of WT and Phd2–/– cKO pregnant mice taken after sacrifice at gestational day 14.5 and 17.5 (scale bars represent 1 cm). (C) Maternal diastolic and systolic pressures across gestation in WT and Phd2–/– cKO mice (*P < 0.05 relative to the WT at each matching gestational day, unpaired Student’s t test; n ≥ 5 separate pregnant mothers per condition).