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 2

Removal of Phd2 in JZ layer alters placental architecture.

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Removal of Phd2 in JZ layer alters placental architecture. (A) H&E s...
(A) H&E staining of WT (left) and Phd2–/– cKO (right) placentae at gestational day 14.5 (scale bars represent 100 μm). Higher magnifications (scale bars represent 25 μm) show invagination of spongiotrophoblast cells (left insert) and mislocalization of JZ-restricted glycogen cells (middle insert) in the labyrinth layer while MAS staining (right insert) revealed collagen deposits in the JZ layer of Phd2–/– cKO placentae (n = 4 WT and Phd2–/– cKO placentae respectively). (B) Morphometric analysis of placental layers (measured by delineating the total area of each layer) of E14.5 WT and Phd2–/– cKO placentae. Size of labyrinth (L) and junctional zone (JZ) are expressed as percentage of whole placenta (*P < 0.05, 1-way ANOVA, Tukey posttest; n = 4 WT and n = 4 Phd2–/– cKO placentae). (C) Representative IHC staining for CD34 (endothelial cell marker) in E14.5 WT and Phd2–/– cKO placentae (n = 4 WT and Phd2–/– cKO placentae respectively, scale bars represent 50 μm). (D) Representative transmission electron microscopy (TEM) images of the labyrinth of E14.5 WT and Phd2–/– cKO placentae and associated lipid droplet count (*P < 0.05, unpaired Student’s t test; TEM images/placenta; n = 3 WT and n = 3 Phd2–/– cKO placentae). Yellow arrowheads indicate lipid droplets in SII, while red double arrow lines indicate size of maternal sinusoids. D, decidua; FS, fetal sinusoids; GC, glycogen cells; CD, collagen deposits; FBC, fetal blood cell; FEC, fetal endothelial cell; JZ, junctional zone; L, labyrinth; MAS, Masson’s trichrome stain; MS, maternal sinusoids; MBC, maternal blood cells; T, trophoblast cell; SI, syncytiotrophoblast layer I; SII, syncytiotrophoblast layer II; SpT, spongiotrophoblast.