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 8

ACF administration at midgestation of pregnancy corrects 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 at midgestation of pregnancy corrects placental, feta...
(A) Schematic of ACF injection regimen during midgestation (GD10.5–14.5) of pregnancy. (B) Mean arterial blood pressures across gestation in WT and Phd2–/– cKO pregnant mice treated with either PBS or ACF from days 10.5 to 14.5 of gestation (no significant differences relative to WT, 1-way ANOVA, Newman-Keuls post hoc test; n = 4 separate pregnant mothers per condition). (C) Fetal over placental weight ratios at gestational day 17.5 of ACF- and PBS-treated (GD10.5–14.5) mothers (n = 17 embryos of WT pregnant mothers treated with PBS; n = 29 embryos of Phd2–/– cKO pregnant mothers treated with ACF). (D) Representative H&E staining and (E) morphometric analysis of E17.5 placental sections from WT and Phd2–/– cKO pregnant mice treated with either PBS or ACF from GD10.5 to 14.5 (scale bars represent 100 μm). Size of labyrinth (L) and junctional zone (JZ) are expressed as a percentage of whole placenta. (n = 4 WT and 4 Phd2–/– cKO placentae.) D, decidua. (F) H&E staining of decidual maternal SpAs of E17.5 placentae from WT and Phd2–/– cKO pregnant mice after treatment with PBS or ACF from GD10.5 to 14.5 (scale bars represent 25 μm) (dotted lines delineate inner and outer wall of the maternal SpAs). W, wall; L, lumen. (G) Wall thickness and lumen area measurements of decidual SpAs in E17.5 placentae from WT and Phd2–/– cKO pregnant mice treated with either PBS or ACF from GD10.5 to 14.5 (n = 27 SpAs of 6 WT placentae of PBS-treated pregnant mice and n = 27 SpAs of 6 Phd2–/– cKO placentae of ACF-treated pregnant dams).