scholarly journals Identifying Stabilin-1 and Stabilin-2 Double Knockouts in Reproduction and Placentation: A Descriptive Study

2020 ◽  
Vol 21 (19) ◽  
pp. 7235
Author(s):  
Soon-Young Kim ◽  
Eun-Hye Lee ◽  
Eun Na Kim ◽  
Woo-Chan Son ◽  
Yeo Hyang Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Fetal Development ◽  
Knockout Mouse ◽  
Descriptive Study ◽  
Reproductive Capacity ◽  
Placental Development ◽  
Phenotypic Characteristics ◽  
Double Knockout ◽  
Study Offer

The placenta undergoes reconstruction at different times during fetal development to supply oxygen and nutrients required throughout pregnancy. To accommodate the rapid growth of the fetus, small spiral arteries undergo remodeling in the placenta. This remodeling includes apoptosis of endothelial cells that line spiral arteries, which are replaced by trophoblasts of fetal origin. Removal of dead cells is critical during this process. Stabilin-1 (Stab1) and stabilin-2 (Stab2) are important receptors expressed on scavenger cells that absorb and degrade apoptotic cells, and Stab1 is expressed in specific cells of the placenta. However, the role of Stab1 and Stab2 in placental development and maintenance remain unclear. In this study, we assessed Stab1 and Stab2 expression in the placenta and examined the reproductive capacity and placental development using a double-knockout mouse strain lacking both Stab1 and Stab2 (Stab1/2 dKO mice). Most pregnant Stab1/2 dKO female mice did not produce offspring and exhibited placental defects, including decidual hemorrhage and necrosis. Findings of this study offer the first description of the phenotypic characteristics of placentas and embryos of Stab1/2 dKO females during pregnancy, suggesting that Stab1 and Stab2 are involved in placental development and maintenance.

scholarly journals A Potential Role and Contribution of Androgens in Placental Development and Pregnancy

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 644
Author(s):  
Agata M. Parsons ◽  
Gerrit J. Bouma
Keyword(s):  
Fetal Development ◽  
Fetal Loss ◽  
Membrane Receptors ◽  
Placental Development ◽  
Placental Function ◽  
Fetal Physiology ◽  
Estrogen Synthesis ◽  
And Function ◽  
Pregnancy Disorders

Successful pregnancy requires the establishment of a highly regulated maternal–fetal environment. This is achieved through the harmonious regulation of steroid hormones, which modulate both maternal and fetal physiology, and are critical for pregnancy maintenance. Defects in steroidogenesis and steroid signaling can lead to pregnancy disorders or even fetal loss. The placenta is a multifunctional, transitory organ which develops at the maternal–fetal interface, and supports fetal development through endocrine signaling, the transport of nutrients and gas exchange. The placenta has the ability to adapt to adverse environments, including hormonal variations, trying to support fetal development. However, if placental function is impaired, or its capacity to adapt is exceeded, fetal development will be compromised. The goal of this review is to explore the relevance of androgens and androgen signaling during pregnancy, specifically in placental development and function. Often considered a mere precursor to placental estrogen synthesis, the placenta in fact secretes androgens throughout pregnancy, and not only contains the androgen steroid nuclear receptor, but also non-genomic membrane receptors for androgens, suggesting a role of androgen signaling in placental function. Moreover, a number of pregnancy disorders, including pre-eclampsia, gestational diabetes, intrauterine growth restriction, and polycystic ovarian syndrome, are associated with abnormal androgen levels and androgen signaling. Understanding the role of androgens in the placenta will provide a greater understanding of the pathophysiology of pregnancy disorders associated with androgen elevation and its consequences.

scholarly journals Study of Human T21 Placenta Suggests a Potential Role of Mesenchymal Spondin-2 in Placental Vascular Development

Endocrinology ◽  
2019 ◽  
Vol 160 (3) ◽  
pp. 684-698 ◽  
Author(s):  
Pascale Gerbaud ◽  
Padma Murthi ◽  
Jean Guibourdenche ◽  
Fabien Guimiot ◽  
Benoît Sarazin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Biochemical Analysis ◽  
Mesenchymal Cells ◽  
Conditioned Media ◽  
Chromosome 21 ◽  
Placental Development ◽  
Cm Protein ◽  
Protein Array Analysis ◽  
Functional Analyses

Abstract Placental development is particularly altered in trisomy of chromosome 21 (T21)–affected pregnancies. We previously described in T21-affected placentae an abnormal paracrine crosstalk between the villus mesenchymal core and villus trophoblasts. T21-affected placentae are known to be characterized by their hypovascularity. However, the causes of this anomaly remain not fully elucidated. Therefore, the hypothesis of an abnormal paracrine crosstalk between fetal mesenchymal core and placental endothelial cells (PLECs) was evocated. Villus mesenchymal cells from control (CMCs) and T21 placentae (T21MCs) were isolated and grown in culture to allow their characterization and collection of conditioned media for functional analyses (CMC-CM and T21MC-CM, respectively). Interestingly, PLEC proliferation and branching ability were less stimulated by T21MC-CM than by CMC-CM. Protein array analysis identified secreted proangiogenic growth factors in CMC-CM, which were reduced in T21MC-CM. Combined mass spectrometry and biochemical analysis identified spondin-2 as a factor decreased in T21MC-CM compared with CMC-CM. We found that exogenous spondin-2 stimulated PLEC proliferation and established that T21MC-CM supplemented with spondin-2 recovered conditioned media ability to induce PLEC proliferation and angiogenesis. Hence, this study demonstrates a crosstalk between villus mesenchymal and fetal endothelial cells, in which spondin-2 secreted from mesenchymal cells plays a central role in placental vascular functions. Furthermore, our results also suggest that a reduction in spondin-2 secretion may contribute to the pathogenesis of T21 placental hypovascularity.

scholarly journals Individual Somatic H1 Subtypes Are Dispensable for Mouse Development Even in Mice Lacking the H10Replacement Subtype

2001 ◽  
Vol 21 (23) ◽  
pp. 7933-7943 ◽  
Author(s):  
Yuhong Fan ◽  
Allen Sirotkin ◽  
Robert G. Russell ◽  
Julianna Ayala ◽  
Arthur I. Skoultchi
Keyword(s):  
Knockout Mice ◽  
Knockout Mouse ◽  
Embryonic Stem ◽  
Mouse Development ◽  
Double Knockout ◽  
Linker Histones ◽  
Deficient Mice ◽  
Mouse Lines

ABSTRACT H1 linker histones are involved in facilitating the folding of chromatin into a 30-nm fiber. Mice contain eight H1 subtypes that differ in amino acid sequence and expression during development. Previous work showed that mice lacking H10, the most divergent subtype, develop normally. Examination of chromatin in H10−/− mice showed that other H1s, especially H1c, H1d, and H1e, compensate for the loss of H10 to maintain a normal H1-to-nucleosome stoichiometry, even in tissues that normally contain abundant amounts of H10 (A. M. Sirotkin et al., Proc. Natl. Acad. Sci. USA 92:6434–6438, 1995). To further investigate the in vivo role of individual mammalian H1s in development, we generated mice lacking H1c, H1d, or H1e by homologous recombination in mouse embryonic stem cells. Mice lacking any one of these H1 subtypes grew and reproduced normally and did not exhibit any obvious phenotype. To determine whether one of these H1s, in particular, was responsible for the compensation present in H10−/− mice, each of the three H1 knockout mouse lines was bred with H10 knockout mice to generate H1c/H10, H1d/H10, or H1e/H10double-knockout mice. Each of these doubly H1-deficient mice also was fertile and exhibited no anatomic or histological abnormalities. Chromatin from the three double-knockout strains showed no significant change in the ratio of total H1 to nucleosomes. These results suggest that any individual H1 subtype is dispensable for mouse development and that loss of even two subtypes is tolerated if a normal H1-to-nucleosome stoichiometry is maintained. Multiple compound H1 knockouts will probably be needed to disrupt the compensation within this multigene family.

scholarly journals The influence of maternal nutrient restriction in early to mid-pregnancy on placental and fetal development in sheep

1999 ◽  
Vol 58 (2) ◽  
pp. 283-288 ◽  
Author(s):  
L. Heasman ◽  
L. Clarke ◽  
T. J. Stephenson ◽  
M. E. Symonds
Keyword(s):  
Fetal Development ◽  
Growth And Development ◽  
Maternal Nutrition ◽  
Placental Weight ◽  
Energy Requirements ◽  
Nutrient Restriction ◽  
Placental Development ◽  
Fetal Size ◽  
Size At Birth

Placental weight is a primary factor determining size at birth in many species. In sheep, placental weight peaks at approximately mid-gestation, with structural remodelling occurring over the second half of pregnancy to meet the increasing nutritional demands of the growing fetus. Numerous factors influence placental growth and development in sheep, and many workers (see Kelly, 1992) have investigated the role of maternal nutrition as a regulator of placental and fetal size. We have studied the effects of feeding ewes approximately 50 % of their recommended energy requirements during early to mid-pregnancy on fetal and placental indices measured at mid-gestation (i.e. 80 d) and close to term (i.e. 145 d). Maternal nutrient restriction is associated with a reduction in placental weight at 80 d, but an increase in placental weight at 145 d of gestation, compared with ewes fed adequately in early pregnancy. No significant effect on fetal weight was observed at either 80 or 145 d gestation, although differences in body dimensions and the insulin-like growth factor-1 axis were found in lambs from nutrient-restricted ewes delivered close to term. Maternal nutrition during pregnancy plays a pivotal role in the regulation of fetal and placental development in sheep, and therefore has the potential to influence both short- and longer-term health outcomes.

172. A MODEST INFLAMMATORY INSULT IN THE PRE-IMPLANTATION PERIOD ALTERS OVIDUCT CYTOKINE EXPRESSION AND PROGRAMS FETAL DEVELOPMENT

2010 ◽  
Vol 22 (9) ◽  
pp. 90 ◽  
Author(s):  
P. Y. Chin ◽  
J. G. Thompson ◽  
S. A. Robertson
Keyword(s):  
Embryo Development ◽  
Fetal Development ◽  
Underlying Mechanism ◽  
Cell Number ◽  
Cytokine Expression ◽  
Placental Development ◽  
Inflammatory Insult ◽  
Implantation Period

The cytokine milieu surrounding the pre-implantation embryo contributes to programming optimal embryo development. Perturbations to the maternal environment such as infection and inflammation during the pre-implantation period can influence cytokine synthesis and may cause changes in embryo development that compromise pregnancy outcome. We aimed to investigate the effect of an inflammatory insult with LPS during the pre-implantation period on later fetal development and the role of oviduct cytokine expression in mediating this response. LPS (at various doses of 0.5–62.5 μg) was administered i.p. to C57Bl/6 mice on both day 3 and day 4 post coitum (pc). The effects of treatment on day 4 blastocysts and day 18 fetal development were analysed. Blastocysts from LPS-treated mothers showed reduced viability and smaller total cell number, but were only significant when doses of >12.5 μg LPS were administered. This was not a direct effect of LPS, as no effect of LPS on embryo development in vitro was seen, even at very high LPS concentrations (25 μg/mL). At day 18 pc, pregnancy rates and the number of viable fetuses, as well as fetal and placenta weights were all reduced after low dose LPS treatment (0.5 μg) compared to control PBS-treated females. qPCR analysis of day 4 oviduct tissue revealed that administration of 12.5ug of LPS resulted in increased mRNA expression of cytokines including IL6, TNFA, IL1B, IFNG, IL10 and LIF. Our findings show that a modest pro-inflammatory insult with LPS in the pre-implantation period programs the embryo for later adverse effects on fetal and placental development. The effects of LPS appear to be mediated indirectly via the maternal tract, and altered oviduct cytokine expression which impairs pre-implantation embryo development is implicated as the underlying mechanism. This model will now be utilised to investigate the potential role of specific inflammatory cytokines TNFA and IFNG in mediating this response.

Abstract 3917: Role of Endothelial Cell-Selective Adhesion Molecule in the Progression of Atherosclerosis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Michihiko Inoue ◽  
Tatsuro Ishida ◽  
Tetsuya Hara ◽  
Cangara M Husni ◽  
Li Sun ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Adhesion Molecule ◽  
Lesion Size ◽  
Macrophage Infiltration ◽  
Immunoglobulin Superfamily ◽  
Double Knockout ◽  
Aortic Sinus

Backgrounds : Endothelial cell-selective adhesion molecule (ESAM) is a new member of the immunoglobulin superfamily, which is expressed in vascular endothelial cells. Although ESAM has been shown to mediate homohilic adhesion between endothelial cells, the interaction of ESAM and hematopoietic cells has not been ingestigated. Also, the role of ESAM in atherosclerosis remains unclear. In this study, we assessed the role of ESAM in monocyte/ macarophage infiltration, and examined effects of ESAM inactivation in the development atherosclerosis using a murine model of atherosclerosis. Methods and Results : ESAM−/− mice were bred with apoE−/− mice to generate the double knockout mice, and the lesion size of aortic sinus was evaluated histologically between ESAM+/+ apoE−/− and ESAM−/− apoE+/+ mice. Plasma lipid profile was not affected by ESAM deficiency. However, the lesion size was markedly attenuated in ESAM−/− apoE−/− mice compared to ESAM+/+apoE−/− mice. The percentage of MOMA-2-stained area in the aortic sinus lesions was significantly smaller in ESAM-/-apoE−/− mice than in ESAM+/+apoE−/− mice, suggesting that ESAM deficiency reduced the macrophage infiltration in the atheroma. To clarify the mechanism for the reduced macrophage content in the plaque, in vitro adhesion- and transendothelial migration assays were performed between cultured endothelial monolayers and monocyte/macrophage cell line THP-1 cells utilizing siRNA-mediated knockdown of ESAM. These assays revealed that ESAM deficiency in endothelial cells resulted in decreases in monocyte adhesion to the endothelial cells as well as transendothelialmigration. THP-1 cells did not express ESAM, but directly bound to the recommbinant ESAM protein-coated culture plates. Conclusion : ESAM modulates macrophage infiltration into the atheroma through interaction with unidentified ligand(s) on monocytes. ESAM inactivation can reduce susceptibility to atherosclerosis.

scholarly journals Role of MAdCAM-1-Expressing High Endothelial Venule-Like Vessels in Colitis Induced in Mice Lacking Sulfotransferases Catalyzing L-Selectin Ligand Biosynthesis

2018 ◽  
Vol 66 (6) ◽  
pp. 415-425 ◽  
Author(s):  
Shulin Low ◽  
Jotaro Hirakawa ◽  
Hitomi Hoshino ◽  
Kenji Uchimura ◽  
Hiroto Kawashima ◽  
...  
Keyword(s):  
Knockout Mouse ◽  
Inflammatory Cells ◽  
Chronic Inflammatory Disease ◽  
Sialyl Lewis X ◽  
High Endothelial Venule ◽  
Double Knockout ◽  
Double Knockout Mouse ◽  
Selectin Ligand ◽  
Mononuclear Cell Infiltrates

Ulcerative colitis (UC) is a chronic inflammatory disease histologically characterized by diffuse mononuclear cell infiltrates in colonic mucosa. These inflammatory cells are considered to be recruited via high endothelial venule (HEV)-like vessels displaying mucosal addressin cell adhesion molecule 1 (MAdCAM-1), the ligand for α4β7 integrin, and/or peripheral lymph node addressin (PNAd), an L-selectin ligand. 6- O-sulfation of N-acetylglucosamine in the carbohydrate moiety of PNAd is catalyzed exclusively by N-acetylglucosamine-6- O-sulfotransferase 1 (GlcNAc6ST-1) and GlcNAc6ST-2. To determine the role of 6- O-sulfation of N-acetylglucosamine on HEV-like vessels in UC, we used a chronic dextran sulfate sodium–induced colitis model using mice deficient in both GlcNAc6ST-1 and GlcNAc6ST-2. We found that more inflammatory cells, with expression of tumor necrosis factor α, were infiltrated in double knockout mouse colitis compared with that in wild-type mice. Moreover, the number of MAdCAM-1-positive vessels was increased in double knockout mouse colitis, and these vessels were bound by E-selectin•IgM chimeras that bind to unsulfated sialyl Lewis X (sLeX). These findings suggest that interactions between MAdCAM-1 and α4β7 integrin and/or unsulfated sLeX and L-selectin may become a dominant mechanism for inflammatory cell recruitment in the absence of 6-sulfo sLeX and contribute to more severe colitis phenotypes seen in double knockout mice.

Abstract 380: Vascular Pcsk9: A Mediator for Atherogenesis Independent of LDL Receptor

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Hua Sun ◽  
Michael Tan ◽  
Ba-bie Teng
Keyword(s):  
Endothelial Cells ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Degradation Process ◽  
Double Knockout ◽  
Aortic Endothelial Cells ◽  
Apob Mrna ◽  
Pcsk9 Gene ◽  
Atherosclerotic Lesions

PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases the LDL levels by binding to hepatocyte LDL receptors (LDLR) and subjects it to degradation. We show that PCSK9 regulates apolipoprotein B (apoB) production by inhibiting its degradation process via the autophagic pathway, irrespective of the presence of LDLR. In addition to the role of PCSK9 in promoting hyperlipidemia, we hypothesized that vascular-PCSK9 in endothelial cells (EC) plays a role in initiating atherogenesis, irrespective of the presence of LDL receptor. Our laboratory has generated double knockout mice lacking both LDLR and Apobec1 (apoB mRNA editing enzyme), named LDb, Ldlr-/-Apobec1-/-. They have the lipoprotein phenotype mimics human with hyperlipidemia; elevated levels of VLDL and LDL with low levels of HDL. They develop atherosclerotic lesions spontaneously. To investigate the role of PCSK9 in atherogenesis, we deleted Pcsk9 gene from LDb mice to generate the triple knockout mice (named LTp, Ldlr-/-Apobec1-/-Pcsk9-/-). In comparison to LDb mice (n=14), the LTp mice (n=8) had significantly decreased levels of cholesterol (387±10 vs. 313±14 mg/dl; p<0.0008) and triglyceride (304±15 vs. 204±2.3 mg/dl; p<0.0002). However, despite their high cholesterol levels at over 300 mg/dl, the atherosclerotic lesions in LTp mice were significantly decreased in comparison to LDb mice (8.8%±3.5 vs. 24%±3.3, p=0.004, n=5 vs. 5). We hypothesized that vascular PCSK9 regulates the development of atherosclerosis. We incubated LDL containing PCSK9 (LDL/PCSK9) on primary aortic endothelial cells (EC) obtained from LDb or LTp to study the effects of LDL/PCSK9 on inflammation. We show that LDL/PCSK9 could not induce the expressions of Lox-1, TLR-2, or ICAM-1 in EC from LTp, resulting in absence responses on proinflammatory markers (CCL2 and CCL7) and autophagic molecules (p62 and TRAF6). In conclusion, our results suggest that vascular PCSK9 play an essential role in atherogenesis.

Role of IL-6 in an IL-10 and IL-4 Double Knockout Mouse Model Uniquely Susceptible to Acetaminophen-Induced Liver Injury†

2007 ◽  
Vol 20 (2) ◽  
pp. 208-216 ◽  
Author(s):  
Mohammed Bourdi ◽  
Daniel P. Eiras ◽  
Michael P. Holt ◽  
Marie R. Webster ◽  
Timothy P. Reilly ◽  
...  
Keyword(s):  
Liver Injury ◽  
Mouse Model ◽  
Knockout Mouse ◽  
Double Knockout ◽  
Knockout Mouse Model ◽  
Double Knockout Mouse
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