Impaired decidual natural killer cell regulation of vascular remodelling in early human pregnancies with high uterine artery resistance (original) (raw)
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Journal of leukocyte biology, 2015
During pregnancy, a specialized type of NK cell accumulates in the lining of the uterus (decidua) and interacts with semiallogeneic fetal trophoblast cells. dNK cells are functionally and phenotypically distinct from PB NK and are implicated in regulation of trophoblast transformation of the uterine spiral arteries, which if inadequately performed, can result in pregnancy disorders. Here, we have used uterine artery Doppler RI in the first trimester of pregnancy as a proxy measure of the extent of transformation of the spiral arteries to identify pregnancies with a high RI, indicative of impaired spiral artery remodeling. We have used flow cytometry to examine dNK cells isolated from these pregnancies compared with those from pregnancies with a normal RI. We report a reduction in the proportion of dNK cells from high RI pregnancies expressing KIR2DL/S1,3,5 and LILRB1, receptors for HLA-C and HLA-G on trophoblast. Decreased LILRB1 expression in the decidua was examined by receptor bl...
Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstétrique et gynécologie du Canada : JOGC, 2008
Adequate invasion of the human placenta during the first weeks of pregnancy is a critical step in ensuring both fetal and maternal health. A rapidly expanding body of evidence suggests that decidual natural killer (dNK) cells, a distinct population of CD56brightCD16- lymphocytes, are key regulators of this complex process. Experiments using murine models and in vitro evidence using human tissue cultures suggest that dNK cells modulate extravillous trophoblast (EVT) invasion and remodelling of maternal spiral arteries via both contact-dependent and contact-independent mechanisms. In addition, the differential expression of surface receptors by dNK cells may have a role in determining reproductive success through modulation of the maternal immune system at the time of implantation and placentation. The roles of cytokines, chemokines, and growth factors secreted by dNK cells and their influence on EVT migration, invasion, and pseudovasculogenesis are of particular interest. We reviewed...
Uterine natural killer cells initiate spiral artery remodeling in human pregnancy
The FASEB Journal, 2012
Uterine spiral artery remodeling is required for successful human pregnancy; impaired remodeling is associated with pregnancy complications, including late miscarriage, preeclampsia, and fetal growth restriction. The molecular triggers of remodeling are not known, but it is now clear that there are "trophoblastindependent" and "trophoblast-dependent" stages. Uterine natural killer (uNK) cells are abundant in decidualized endometrium in early pregnancy; they surround spiral arteries and secrete a range of angiogenic growth factors. We hypothesized that uNK cells mediate the initial stages of spiral artery remodeling. uNK cells and extravillous trophoblast (EVT) cells were isolated from early pregnancy decidua and placenta. Chorionic plate arteries from full-term placentas and spiral arteries from nonpregnant myometrium were cultured with angiogenic growth factors or conditioned medium (CM) from uNK cells or EVT or uNK cell/EVT cocultures. In both vessel models, uNK cell CM induced disruption of vascular smooth muscle cells (VSMCs) and breakdown of extracellular matrix components. Angiopoietin (Ang)-1, Ang-2, interferon-␥, and VEGF-C also disrupted VSMC integrity with an Ang-2 inhibitor abrogating the effect of uNK cell CM. These results provide compelling evidence that uNK cells contribute to the early stages of spiral artery remodeling; failure of this process could contribute to pregnancy pathologynatural killer cells initiate spiral artery remodeling in human pregnancy. FASEB J.
Review: Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua
Placenta, 2010
Leukocytes comprise approximately 30-40% of decidual stromal cells in early human pregnancy. The major leukocyte component is the uterine natural killer (uNK) cells. Despite over 20 years of research the functional role of these cells in situ remains unknown although they have been proposed to play roles in immunotolerance, regulation of trophoblast invasion and remodeling of the spiral arteries. Herein we review the functional roles of this important decidual cell type.
Cellular & molecular immunology, 2015
Decidual natural killer (dNK) cells express an array of activation receptors to regulate placental immunity and development during early pregnancy. We investigated the functional character of human dNK cells during the first and second trimester of gestation and the interaction between dNK and trophoblast cells. Although the frequency of CD56(+)CD16(-) dNK among the total CD45(+) leukocytes did not change over this period, the expression of the activating receptors, NKp80 and NKG2D, was greatly upregulated. We observed a significantly higher number of extravillous trophoblast cells in proximity to the dNK cells in the first trimester in comparison with the second trimester decidua. NKG2D expression by first trimester dNK cells was decreased when co-cultured with the HTR-8 trophoblast cell line. In the second trimester, functional markers of dNK activation, i.e., angiogenic factor production (e.g., vascular endothelial growth factor, interleukin-8, interferon-gamma), remained stable ...
Angiogenic factors and natural killer (NK) cells in the pathogenesis of preeclampsia
Journal of reproductive immunology, 2007
Preeclampsia is a pregnancy-specific complex disease in which numerous genetic, immunological and environmental factors interact. Characterized by new onset hypertension, proteinuria and edema after 20 weeks of gestation, preeclampsia is often complicated by small-for-gestational-age (SGA) babies and preterm delivery, and is therefore a significant cause of maternal and fetal morbidity and mortality. The only definitive treatment of preeclampsia is delivery of the placenta. Recent data suggest that the anti-angiogenic state induced by excess circulating anti-angiogenic factors of placental origin may be responsible for the clinical signs and symptoms of preeclampsia. Natural killer (NK) cells at the maternal/fetal interface, which are thought to play an important role in normal placental development, have been noted recently to induce angiogenic factors and vascular remodeling. Moreover, genetic studies suggest that susceptibility to preeclampsia may be influenced by polymorphic HLA-C ligands and killer cell receptors (KIR) present on NK cells. This review summarizes our current understanding of the role of angiogenic factors and NK cells in the pathogenesis of preeclampsia.
Science in China Series C: Life Sciences, 2008
VEGF-A mRNA, but not Ang2 mRNA, in isolated uNK cells in human decidua of the first-trimester gestation by combination of LCM and Nested-PCR. Our study indicated that uNK cells, through expressing VEGF-A, may play an important role in the angiogenic response at the time of human decidualization and early placenta development. uterine natural killer cells, decidua, angiogenesis, VEGF, Ang2
The American Journal of Pathology, 2007
Preeclampsia complicates 5 to 10% of pregnancies and is a leading cause of maternal and fetal mortality and morbidity. Although the cause is unknown, inadequate invasion and remodeling of maternal uterine arteries by extravillous trophoblasts (EVTs) in the first trimester is a common feature. Uterine spiral artery resistance as detected by Doppler ultrasound is commonly used in the second trimester to identify pregnancies destined to develop preeclampsia. Correlation between high uterine resistance and the failure of trophoblast invasion has been reported as early as 12 weeks. However, the reason for this failure has not been established. Understanding the processes involved would significantly improve our diagnostic potential. In this study, we correlated increased first trimester uterine artery resistance with a biological abnormality in trophoblast function. EVTs derived from high-resistance pregnancies were more sensitive to apoptotic stimuli than those from normal-resistance pregnancies. Survival of EVTs from high-resistance pregnancies could be increased by nitric oxide, whereas inhibition of nitric oxide in cells from normal-resistance pregnancies increased apoptotic sensitivity. This predates the onset of symptoms by several weeks and provides evidence for a mechanism responsible for the incomplete uterine vessel remodeling and the differences in artery resistance between preeclamptic and normal pregnancies.
Innate immune cells in the placental bed in healthy pregnancy and preeclampsia
Placenta, 2018
Immune cells in the placental bed are important for adequate development of the placental bed. The most prominent immune cells in the placental bed early in pregnancy are uterine natural killer cells (uNK) cells and macrophages. Also dendritic cells and mast cells can be found in the early placental bed. These cells not only have an immune regulatory function, but are also involved in the regulation of trophoblast invasion, angiogenesis and spiral artery remodeling. In preeclampsia, one of the major complications of pregnancy, decreased trophoblast invasion and spiral artery remodeling has been found. This is associated with decreased numbers of uNK cells, increased numbers of macrophages around the spiral arteries and similar or increased numbers of dendritic cells in the placental bed. In this review, we discuss the current insights in the functions of uNK cells, macrophages, dendritic cells and mast cells in the placental bed in humans during healthy pregnancy and during preeclam...
Uterine natural killer cells and successful pregnancy: from mouse experiments to human physiology
Exploration of Immunology
Uterine natural killer (uNK) cells, a specific type of natural killer (NK) cells, are important cells at the foeto-maternal interface in humans as well as in mice. uNK cells are part of the innate lymphoid cells group 1. Especially in the mouse, but also in the rat, many in vivo studies have been performed to evaluate the role of uNK cells in placental development. These studies have shown that uNK cells are not indispensable to pregnancy, but that they play an important role in optimal decidual angiogenesis in early pregnancy, trophoblast invasion and spiral artery remodelling in the mouse placenta. Based on the mouse studies, various in vitro studies, as well as immunohistological studies of the human placenta from elective abortions, have shown that uNK cells have similar functions in the human placenta. In the present narrative review, the role of the uNK cells in the development of the mouse and rat placenta will be discussed first. Thereafter, studies on the role of human uNK ...