Inactivation of maternal Hif-1α at mid-pregnancy causes placental defects and deficits in oxygen delivery to the fetal organs under hypoxic stress

Abstract

A critical transition occurs near mid-gestation of mammalian pregnancy. Prior to this transition, low concentrations of oxygen (hypoxia) signaling through Hypoxia Inducible Factor (HIF) functions as a morphogen for the placenta and fetal organs. Subsequently, functional coupling of the placenta and fetal cardiovascular system for oxygen (O2) transport is required to support the continued growth and development of the fetus. Here we tested the hypothesis that Hif-1α is required in maternal cells for placental morphogenesis and function. We used Tamoxifen-inducible Cre-Lox to inactivate Hif-1α in maternal tissues at E8.5 (MATcKO), and used ODD-Luciferase as a reporter of hypoxia in placenta and fetal tissues. MATcKO of Hif-1α reduced the number of uterine natural killer (uNK) cells and Tpbpa-positve trophoblast cells in the maternal decidua at E13.5 −15.5. There were dynamic changes in all three layers of E13.5–15.5 MATcKO placenta. Of note was the under-development of the labyrinth at E15.5 associated with reduced Ki67 and increased TUNEL staining consistent with reduced cell proliferation and increased apoptosis. Labyrinth defects were particularly evident in placentas connected to effectively HIF-1α heterozygous null embryos. MATcKO had no effect on basal ODD-Luciferase activity in fetal organs (heart, liver, brain) at any stage, but at E13.5 −15.5 resulted in enhanced induction of the ODD-Luciferase hypoxia reporter when the dam’s inspired O2 was reduced to 8% for 4 hours. MATcKO also slowed the growth after E13.5 of fetuses that were effectively heterozygous for Hif-1α, with most being non-viable at E15.5. The hearts of these E15.5 fetuses were abnormal with reduction in size, thickened epicardium and mesenchymal septum. We conclude that maternal HIF-1α is required for placentation, specifically, recruitment of uNK and trophoblast cells into the maternal decidua and other trophoblast cell behaviors. The placental defects render the fetus vulnerable to O2 deprivation after mid-gestation.

Deletion of Prl7d1 causes placental defects at mid‐pregnancy in mice

“…Hif-1α results in a decrease in the number of uNK cells and impaired oxygen delivery to the fetus at E13.5-15.5 (Kenchegowda et al, 2017). Overall, this analysis indicates that disruption of Prl7d1 has a profound effect on signaling in the female placenta.…”

“…Further, Wnt2‐ deficient mice exhibit decreased numbers of fetal capillaries and fibrinoid deposition in the placenta, and as a result, approximately 50% of pups die perinatally (Monkley, Delaney, Pennisi, Christiansen, & Wainwright, ). Inactivation of maternal Hif‐1α results in a decrease in the number of uNK cells and impaired oxygen delivery to the fetus at E13.5–15.5 (Kenchegowda et al, ). Overall, this analysis indicates that disruption of Prl7d1 has a profound effect on signaling in the female placenta.…”

“…In addition, the placenta itself also synthesizes a variety of hormones, enzymes, and cytokines, which are mostly encoded by placenta‐specific genes, to adjust placental physiology and mediate gas exchange, nutrient uptake, and waste elimination between the mother and fetus (Bu, Alam, Dhakal, Vivian, & Soares, ; Burton & Fowden, ; Naruse et al, ; Simmons, Rawn, Davies, Hughes, & Cross, ). Emerging evidence suggests that some internal or external factors can target certain placenta‐specific genes, and therefore may impair placenta formation and function, ultimately contributing to the etiology of many pregnancy‐related diseases such as pre‐eclampsia, intrauterine growth restriction, and abortion; this can have consequences for the long‐term health of the individual (Huynh, Dawson, Roberts, & Bentley‐Lewis, ; Kenchegowda, Natale, Lemus, Natale, & Fisher, ; Sones et al, ). Thus, decoding the functions of these placental genes will help to elucidate placental physiology and pregnancy‐related diseases.…”

“…the long-term health of the individual (Huynh, Dawson, Roberts, & Bentley-Lewis, 2015;Kenchegowda, Natale, Lemus, Natale, & Fisher, 2017;Sones et al, 2018). Thus, decoding the functions of these placental genes will help to elucidate placental physiology and pregnancy-related diseases.…”

The platelet‐derived growth factor receptor alpha promoter‐directed expression of cre recombinase in mouse placenta

“…Using the promoter from a specific gene or a chimeric DNA construct to direct Cre expression in specific cells is the key component of the Cre/loxP system. Although several promoters have been used to target transgene expression in trophoblast lineages, to our knowledge very few studies have been conducted using inducible Cre/loxP specifically for placental research . Furthermore, in both of these models, broadly expressed Cre transgenic animals were utilized, complicating the interpretation of the results.…”