The metrial gland is more than a mesometrial lymphoid aggregate of pregnancy
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Placentation
Trophoblast
Spiral artery
Natural killer (NK) cells are recruited into the uterine stroma during establishment of the hemochorial placenta and are proposed regulators of uterine spiral artery remodeling. Failures in uterine spiral artery remodeling are linked to diseases of pregnancy. This prompted an investigation of the involvement of NK cells in placentation. NK cell depletion decreased the delivery of proangiogenic factors and delayed uterine spiral artery development, leading to decreased oxygen tension at the placentation site, stabilized hypoxia-inducible factor 1A protein, and redirected trophoblast differentiation to an invasive phenotype. Trophoblast cells replaced the endothelium of uterine spiral arteries extending the depth of the placental vascular bed and accelerating vessel remodeling. Hypoxia-regulated trophoblast lineage decisions, including expansion of invasive trophoblast, could be reproduced in vitro by using rat trophoblast stem cells and were dependent on hypoxia-inducible factor signaling. We conclude that NK cells guide hemochorial placentation through controlling a hypoxia-sensitive adaptive reflex regulating trophoblast lineage decisions.
Placentation
Spiral artery
Trophoblast
Hypoxia
Hypoxia-Inducible Factors
Oxygen tension
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Placentation
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Spiral artery
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Placentation
Trophoblast
Cytotrophoblast
Decidua
Spiral artery
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Hemochorial placentation is characterized by the development of trophoblast cells specialized to interact with the uterine vascular bed. We utilized trophoblast stem (TS) cell and mutant rat models to investigate regulatory mechanisms controlling trophoblast cell development. TS cell differentiation was characterized by acquisition of transcript signatures indicative of an endothelial cell-like phenotype, which was highlighted by the expression of anticoagulation factors including tissue factor pathway inhibitor (TFPI). TFPI localized to invasive endovascular trophoblast cells of the rat placentation site. Disruption of TFPI in rat TS cells interfered with development of the endothelial cell-like endovascular trophoblast cell phenotype. Similarly, TFPI was expressed in human invasive/extravillous trophoblast (EVT) cells situated within first-trimester human placental tissues and following differentiation of human TS cells. TFPI was required for human TS cell differentiation to EVT cells. We next investigated the physiological relevance of TFPI at the placentation site. Genome-edited global TFPI loss-of-function rat models revealed critical roles for TFPI in embryonic development, resulting in homogeneous midgestation lethality prohibiting analysis of the role of TFPI as a regulator of the late-gestation wave of intrauterine trophoblast cell invasion. In vivo trophoblast-specific TFPI knockdown was compatible with pregnancy but had profound effects at the uterine-placental interface, including restriction of the depth of intrauterine trophoblast cell invasion while leading to the accumulation of natural killer cells and increased fibrin deposition. Collectively, the experimentation implicates TFPI as a conserved regulator of invasive/EVT cell development, uterine spiral artery remodeling, and hemostasis at the maternal-fetal interface.
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Normal embryonic development is dependent upon a sufficient oxygen, nutrient and waste exchange through the placenta. In primates including humans, this exchange is attained by successful haemochorial placentation which requires the transformation of maternal intramyometrial spiral arterioles by trophoblast invasion to gain uteroplacental circulation, and establishment and maintenance of a competent fetoplacental vasculature. Thus, trophoblast and endothelial cell differentiation, proliferation and invasion occurring during placentation have to be tightly regulated. This review focuses on the diverse developmental steps during haemochorial placentation in humans and other primates and the possible involvement of angiogenic growth factors (vascular endothelial growth factor (VEGF) and angiopoietins (Ang)) in these processes, highlighting the importance of specific actions of angiogenic ligand-receptor pairs. It is hypothesized that VEGF/VEGF-R1 and Ang-1/Tie receptor 2 (Tie-2) may regulate trophoblast differentiation and invasion; VEGF/VEGF-R2 and Ang-1/Tie-2 may promote fetoplacental vascular development and stabilization; and Ang-2/Tie-2 may be involved in maternal vascular remodelling. The importance of a tight regulation of angiogenic factors and their endogenous antagonists for normal development of the placenta is demonstrated by failure of this system, resulting in abnormal placenta vascularization and trophoblast invasion associated with intrauterine growth retardation or pre-eclampsia.
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Angiopoietin receptor
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Trophoblast invasion is a key process during human placentation. This event constitutes the basis of the conversion of the uterine spiral arteries, a process which allows an adequate vascular connection between the intervillous space and the maternal blood flow. Trophoblast invasion is transient, with stringent spatial and temporal control. Preeclampsia, a leading cause of maternal and fetal mortality and morbidity, is associated with decreased, shallow trophoblastic invasion. In this article, we review the molecular mechanisms of trophoblast invasion, and its mechanisms of regulation. Insights into the etiopathogenesis of preeclampsia will also be detailed.
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Trophoblast
Spiral artery
Intervillous space
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Introduction The migration of trophoblast cells during the first trimester of pregnancy is crucial to placentation process. Defective migration of trophoblastic cells may affect the remodelling (pseduovasculogenesis) of spiral arteries resulting in Hypoxia/Reoxygenation (H/R) episodes. These repeated H/R events can leads to oxidative stress and release of anti‐angiogenic, anti‐inflammatory and pro‐oxidant factors in maternal circulation causing endothelial dysfunction resulting in adverse pregnancy outcomes like preeclampsia and fetal growth restriction. The anti‐inflammatory, pro‐angiogenic and pro‐migratory effect of H 2 S on endothelial cells have been documented in literature. So we hypothesized that H 2 S or its mimics (NaHS) may also affect the migration capacity of trophoblast cells during placentation. Methods The immortalized first trimester extravillous trophoblast cell line (HTR‐8/SVneo) were given various treatments like 50μM NaHS, Hypoxia/Reoxygenation [H/R (one and two cycles)] and Hypoxia/Reoxygenation supplemented with 50μM NaHS. The cell migration was assessed using wound scratch assay following these various exposures. The percentage wound area covered was assessed in all groups. The difference in wound covered area was statistically analysed. [ten different zone in triplicate (i.e. thirty) were used for calculating the wound areas] Results The percentage of wound covered area (rate of migration) increased in cells which received 50μM NaHS [control (32.8%), NaHS (67.5%)] whereas it reduced to 8.7% in Hypoxia/Reoxygenation one cycle exposed cells and more so (−18.9%) in the cells which received two cycles of Hypoxia/Reoxygenation. However the cells which received Hypoxia/Reoxygenation (one cycle and two cycles) and showed reduced migration, improved their rate of migration when supplemented with 50μM NaHS. [one cycle H/R (8.7%), one cycle H/R+NaHS (39.8) and two cycles H/R (−18.9%), two cycles H/R+NaHS (29.5%)]. The difference in wound covered area among various groups was statistically significant [(control vs NaHS; p<0.001, control vs one cycle H/R; p<0.001, control vs two cycle H/R; p<0.001, one cycle H/R vs one cycle H/R+NaHS; p <0.001, two cycle H/R vs two cycles H/R+NaHS; p<0.001 (one‐way ANOVA with Bonferroni correction)]. Conclusion These results imply that H 2 S may promote the migration of trophoblastic cells, which might then lead to adequate conversion of spiral arteries into wider diameter low resistance vessels having good placental perfusion. In future the role of H 2 S on cellular and molecular factors responsible for cell migration needs to explored. IESC/T‐467/23.12.2014 Support or Funding Information F.8‐397/A‐397/2015/Rs This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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Hypoxia
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Trophoblast migration and invasion through the decidua and maternal uterine spiral arteries are crucial events in placentation. During this process, invasive trophoblast replace vascular endothelial cells as the uterine arteries are remodeled to form more permissive vessels that facilitate adequate blood flow to the growing fetus. Placentation failures resulting from either extensive or shallow trophoblastic invasion can cause pregnancy complications such as preeclampsia, intrauterine growth restriction, placenta creta, gestational trophoblastic disease and even maternal or fetal death. Consequently, the use of experimental animal models such as rats and mice has led to great progress in recent years with regards to the identification of mechanisms and factors that control trophoblast migration kinetics. This review aims to perform a comparative analysis of placentation and the mechanisms and factors that coordinate intrauterine trophoblast migration in humans, rats and mice under physiological and pathological conditions.
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Spiral artery
Decidua
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The rat possesses hemochorial placentation with deep intrauterine trophoblast cell invasion and trophoblast-guided uterine spiral artery remodeling, which resembles human placentation. Uterine spiral arteries are extensively remodeled to deliver sufficient supply of maternal blood and nutrients to the developing fetus. Inadequacies in these key processes negatively impact fetal growth and development. Recent innovations in genome editing combined with effective phenotyping strategies have provided new insights into placental development. Application of these research approaches has highlighted both conserved and species-specific features of hemochorial placentation. The review provides foundational information on rat hemochorial placental development and function during physiological and pathological states, especially as related to the invasive trophoblast cell-guided transformation of uterine spiral arteries. Our goal is to showcase the utility of the rat as a model for in vivo mechanistic investigations targeting regulatory events within the uterine-placental interface.
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Knockout mouse
Conditional gene knockout
Gestational hypertension
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