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  • br The invasion of extravillous trophoblast

    2020-07-27


    The invasion of extravillous trophoblast (EVT) into the decidualized endometrium is crucial in the determination of pregnancy outcome. Inadequate trophoblast invasion not only leads to implantation failure and spontaneous pregnancy loss but also results in the insufficient remodeling of spiral substance p receptor that sits at the epicenter of the great obstetric syndromes, including idiopathic fetal growth restriction (FGR), early-onset preeclampsia,, and preterm birth., The EVTs invade soon after implantation and complete the process around midgestation, penetrating as far as the inner one-third of the myometrium. Although many factors and biomolecules, such as transforming growth factor-β, kisspeptin, hypoxia, and the interaction with immune cells, have been proposed to regulate the invasiveness of the EVTs, their downstream effectors principally converge on a family of matrix metalloproteinase (MMP) enzymes, which break down both matrix and nonmatrix proteins., , MMP-2 and MMP-9 are likely two key players. MMP-2 mediates trophoblast invasion during the early implantation stage up to 7 to 8 weeks of gestation, whereas MMP-9 facilitates subsequent invasion., , , Although the regulation of MMP activity has been widely studied, the mechanisms remain largely unknown. MMPs are controlled at multiple levels. Transcriptional regulation occurs on stimulation by a variety of proinflammatory cytokines, growth factors, and hormones, as well as by interactions between cells or between cells and their surrounding matrix. MMPs are synthesized as precursor zymogens and are posttranslationally modified and folded within the endoplasmic reticulum (ER) before extracellular export or transport to the plasma membrane. Their activation is dependent on sequential proteolysis of the propeptide that blocks the active site and is regulated by a number of factors, including plasmin, MMP intermediates, and other active MMP family members. Furthermore, MMP activity can be modulated by exogenous inhibitors, such as α-macroglobulin and a group of tissue inhibitors of metalloproteinases (TIMPs). The requirement for proteolytic cleavage implies that the conformation of the MMPs is critical for their activation. Hence, posttranslational modifications, such as glycosylation and disulfide bond formation, may serve as novel regulatory pathways under stress conditions that are known to trigger ER stress or the ER unfolded protein response (UPR). All three UPR signaling pathways PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1), can regulate gene expression directly through their downstream transcriptional factors ATF4/C/EBP homologous protein (CHOP), cleaved ATF6, and spliced X-box binding protein 1 (XBP1), respectively. For example, we have demonstrated that expression of placental growth factor is mediated through ATF4 and ATF6β signaling in placenta of early-onset preeclampsia. Proinflammatory cytokines have been demonstrated to suppress trophoblast migration, invasion, and integration, resulting in deficient spiral artery remodeling., , The major source of proinflammatory cytokines in the decidua is the immune cells, of which approximately 70% are decidual natural killer cells and approximately 20% are macrophages. Decidual natural killer cells have a unique phenotype and properties compared with their peripheral blood counterparts and secrete cytokines substance p receptor and other soluble factors to modulate implantation, placental function, and ultimately fetal development. Aberrant behavior of these cells has been suggested to contribute to the pathogenesis of preeclampsia., , , , , However, the mechanisms by which these cytokines inhibit trophoblast invasion remain unknown. Coincidently, proinflammatory cytokines also induce ER stress in other mammalian cell types., , Therefore, we investigated the potential role of ER stress in the regulation of trophoblast MMP-2 activity, thereby modulating EVT invasion during early pregnancy.