Alterations in maternal and fetal heart functions accompany failed spiral arterial remodeling in pregnant mice

Zhang, Jianhong; Adams, Michael; Croy, B. Anne

doi:10.1016/j.ajog.2011.06.008

Cited by 20 publications

(18 citation statements)

References 41 publications

(67 reference statements)

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“…In other mouse models with impaired decidual vascular remodelling, ultrasonography identified anomalous gains in cardiac stroke volume and output with left ventricular dilation as compensatory processes during pregnancy. 46 In contrast to human studies, 5 evidence for spontaneous abortion was not present in B6.Ly49 KD mice. It is possible that genes other than Ly49 contribute to the reproductive alterations seen in B6.Ly49 KD mice.…”

Section: Discussioncontrasting

confidence: 40%

Ly49 receptors activate angiogenic mouse DBA+ uterine natural killer cells

Lima

Rahim

et al. 2014

Cell Mol Immunol

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In humans, specific patterns of killer immunoglobulin-like receptors (KIRs) expressed by uterine natural killer (uNK) cells are linked through HLA-C with pregnancy complications (infertility, recurrent spontaneous abortion, intrauterine growth restriction and preeclampsia). To identify mechanisms underpinning the associations between NK cell activation and pregnancy success, pregnancies were studied in mice with genetic knockdown (KD) of the MHC-activated Ly49 receptor gene family. B6.Ly49 KD pregnancies were compared to normal control B6.Ly49 129 and C57BL/6 (B6) pregnancies. At mid-pregnancy (gestation day (gd9.5)), overall uNK cell (TCRb 2 CD122 1 DBA 1 DX5 2 (DBA 1 DX5 2 )) and TCRb 2 CD122 1 DBA 2 DX5 1 (DBA 2 DX5 1 )) frequencies in pregnant uterus were similar between genotypes. Ly49 KD lowered the normal frequencies of Ly49 1 uNK cells from 90.3% to 47.8% in DBA 2 DX5 1 and 78.8% to 6.3% in DBA 1 DX5 2 uNK cell subtypes. B6.Ly49 KD matings frequently resulted in expanded blastocysts that did not implant (subfertility). B6.Ly49 KD mice that established pregnancy had gestational lengths and litter sizes similar to controls. B6.Ly49 KD neonates, however, were heavier than controls. B6.Ly49 KD implantation sites lagged in early (gd6.5) decidual angiogenesis and were deficient in mid-pregnancy (gd10.5) spiral arterial remodelling. Ultrastructural analyses revealed that B6.Ly49 KD uNK cells had impaired granulogenesis, while immunocytochemistry revealed deficient vascular endothelial cell growth factor (VEGFA) production. Perforin and IFNG expression were normal in B6.Ly49 KD uNK cells. Thus, in normal mouse pregnancies, Ly49 receptor signaling must promote implantation, early decidual angiogenesis and mid-pregnancy vascular remodelling. Disturbances in these functions may underlie the reported genetic associations between human pregnancy complications and the inability of specific conceptus MHCs to engage activating KIR on uNK cells.

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Section: Discussioncontrasting

confidence: 40%

Ly49 receptors activate angiogenic mouse DBA+ uterine natural killer cells

Lima

Rahim

et al. 2014

Cell Mol Immunol

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“…Noteworthy, despite these defects, litters of normal size were born (102–105), except in the Tge26 (100, 101) mice, which display a reproductive deficit. Bone marrow transplantation of NK + T − B − pools before mating restored the defects suggesting a major role of uNK cells more related to vascularization than to tolerance.…”

Section: On Other Important Cellsmentioning

confidence: 99%

Regulatory T-Cells in Pregnancy: Historical Perspective, State of the Art, and Burning Questions

et al. 2014

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In this review, we first revisit the original concept of “suppressor T-cells” in pregnancy, put it in a historical perspective, and then highlight the main data that licensed its resurrection and revision into the concept of “regulatory T-cells” (Tregs) in pregnancy. We review the evidence for a major role of Tregs in murine and human pregnancy and discuss Treg interactions with dendritic and uterine natural killer cells, other players of maternal–fetal tolerance. Finally, we highlight what we consider as the most important questions in the field.

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“…Similarly, does MATcKO of Hif-1α early in gestation affect ODD-Luc activity as an indicator of O 2 metabolism, or O 2 reserve, in later stages of development? The mother, placenta and fetus may adapt to stressors that reduce O 2 transport, such as increase in cardiac output, O 2 carrying capacity, and placental size, vascularity and surface area for O 2 exchange, to maintain the viability of the fetus (Gassmann et al, 2016; Webster and Abela, 2007; Zhang et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

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

Kenchegowda

Natale

Lemus

et al. 2017

Developmental Biology

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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.

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Alterations in maternal and fetal heart functions accompany failed spiral arterial remodeling in pregnant mice

Cited by 20 publications

References 41 publications

Ly49 receptors activate angiogenic mouse DBA+ uterine natural killer cells

Ly49 receptors activate angiogenic mouse DBA+ uterine natural killer cells

Regulatory T-Cells in Pregnancy: Historical Perspective, State of the Art, and Burning Questions

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

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