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
View: Text | PDF
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

×

Figure 7

ACF administration in early pregnancy prevents placental, fetal, and maternal preeclamptic phenotype in JZ-specific Phd2–/– cKO pregnant mice.

Options: View larger image (or click on image) Download as PowerPoint
ACF administration in early pregnancy prevents placental, fetal, and mat...
(A) Schematic of ACF injection regimen (GD7.5–14.5) during early pregnancy. (B) H&E staining of E17.5 placental sections from WT and Phd2–/– cKO pregnant mice treated with either PBS or ACF (scale bars represent 100 μm). (C) Morphometric analysis of E17.5 placentae from WT and Phd2–/– cKO pregnant mice treated with either PBS or ACF. Size of total labyrinth (L) and junctional zone (JZ) areas are expressed as a percentage of whole placenta (*P < 0.05, 1-way ANOVA, Newman-Keuls post hoc test; n = 9 WT placentae, n = 9 Phd2–/– cKO placentae, n = 9 Phd2–/– cKO placentae of ACF-treated pregnant dams). D, decidua. (D) H&E staining of decidual maternal SpAs of E17.5 placentae from WT and Phd2–/– cKO pregnant mice after treatment with PBS or ACF (scale bars represent 25 μm). (Arrows indicate the location of the walls [W], and the dotted lines delineate inner and outer wall of the maternal SpAs.) L, lumen. (E) Wall thickness and lumen area measurements of decidual SpAs in GD17.5 placentae from WT and Phd2–/– cKO pregnant mice treated with either PBS or ACF (***P < 0.001 relative to the WT measurements, 1-way ANOVA, Newman-Keuls post hoc test; n = 17 SpAs of 6 WT placentae, n = 41 SpAs of 12 Phd2–/– cKO placentae, n = 25 SpAs of 12 placentae from ACF-treated Phd2–/– cKO dams). (F) Mean arterial blood pressure across gestation in WT and Phd2–/– cKO pregnant mice treated with either PBS or ACF (*P < 0.05 relative to the Phd2–/– cKO pregnant mice at the corresponding gestational age, 1-way ANOVA, Newman-Keuls post hoc test; n = 4 separate pregnant dams per condition).