Identification Of The Primary Outcomes That Result From Deficient Spiral Arterial Modification In Pregnant Mice

Pre-eclampsia, an acute complication of human pregnancy, is associated with incomplete physiological modification of decidual spiral arteries. This is thought to promote oxidative stress from perfusion/reperfusion of the placenta and to restrict placental and fetal growth. Alymphoid (genotype Rag2 -/-/Il2rg-/-) mice, sufficient in dendritic and myeloid cell functions, lack spiral arterial modification with individual spiral arteries having ∼1.7× the vascular resistance and 0.66× the blood velocity of +/+ mice. Their placentae are not measurably hypoxic and neither placental growth nor fetal survival is impaired and gestational hypertension is not seen. Thus, lymphocytes rather than vascular adaptations appear to be the pivotal contributors to the clinical complications of pre-eclampsia. © 2010 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. 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Update On Pathways Regulating The Activation Of Uterine Natural Killer Cells, Their Interactions With Decidual Spiral Arteries And Homing Of Their Precursors To The Uterus

Virgin adult C57Bl/6J mouse uterus contains a population of small, non-granulated Natural Killer (NK) cells with balanced expression of NK cell activating and inhibiting LY49 receptors. Coincident with blastocyst implantation and decidualization, uterine (u)NK cells become activated. The surface glycoslyation of uNK changes, the cells proliferate and they induce production of interferon (IFN)γ, perforin, serine esterases and other molecules, including angiogenic factors. Mouse strains genetically ablated in uNK cells fail to undergo modification of spiral artery segments that branch from the uterine artery and feed into the placenta and these mice do not sustain a robust decidualization response. IFN-γ is thought, from bone marrow transplantation and therapeutic studies, to be the key uNK-cell derived mediator regulating gene expression in vascular and decidual tissues. Here, we review recent studies showing that IL-15 is the critical cytokine controlling uNK cell differentiation and that uNK cells are activated by either IL-12 or IL-18 and by other factors when both IL-12 and IL-18 are genetically absent from implantation sites. We address possible roles of the IFN-γ regulated gene α2-macroglobulin (α2-M) in regulation of the position of fetal trophoblast within the walls of the spiral arteries, and we discuss approaches that have been successful in evaluating mechanisms involved in homing of mouse uNK cell precursors to the uterus. These approaches maybe applicable to studies in women. Our studies show that complex immuno-physiological events contribute to spiral artery modification by mid-gestation in mice. © 2003 Elsevier Science Ireland Ltd. All rights reserved.592175191Anderson, S.K., Ortaldo, J.R., McVicar, D.W., The ever-expanding Ly49 gene family: Repertoire and signaling (2001) Immunol. 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Uterine Natural Killer Cells: Insights Into Their Cellular And Molecular Biology From Mouse Modelling

In primates, including women, and in rodents, natural killer lymphocytes (NK cells) have a unique relationship with the decidualizing uterus. Implantation sites from genetically modified and transplanted mice have proven useful models for understanding potential mechanisms involved in the recruitment, activation and functions of human CD56bright uterine (u)NK cells. Key findings are reviewed in this article. In mice, uNK precursor cells are recruited from secondary lymphoid tissues and are activated coincident with their uterine arrival. uNK cells proliferate, produce cytokines (interferon gamma (IFN-γ) and interleukin 18 (IL-18) and IL-27), and terminally differentiate into granulated lymphocytes. Many uNK cells proliferate within the myometrium at each implantation site forming a structure, the mesometrial lymphoid aggregate of pregnancy (MLAp) that surrounds blood vessels servicing each placenta. Post-mitotic uNK cells are abundant within decidua basalis; frequently (> 25%) associating with spiral arteries, intramurally and intraluminally. From mid-gestation, numbers of uNK cells decline. Studies of implantation sites in mice lacking uNK cells, IFN-γ, components of IFN-γ-induction and -signalling pathways or IFN-γ-regulated genes indicate that uNK cell-derived IFN-γ is essential in triggering pregnancy-induced spiral artery modification. Decidual maintenance and uNK cell death are additional effects of uNK cell-derived IFN-γ. 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