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    • Abnormalities in placentation in patients with

    2023-01-30

    Abnormalities in placentation in patients with PE appear to be associated with changes in different components of the signaling pathway that mediates cytotrophoblast migration/invasion. Studies have showed that the activation of the Notch signaling pathway is associated with the differentiation and modulation of functions of trophoblast Caffeine through the interaction of the Notch transmembrane receptors (NOTCH1-4) and their respective ligands, DLL1,3,4 and JAG1,2 [29], [33]. An experimental study showed a correlation between the non-expression of the NOTCH-2 receptor and the reduction in the diameter of maternal uterine vessels during placentation, with significant impairment of perfusion [33]. Mutations in the gene encoding STOX1 transcription factor may also be associated with the pathogenesis of PE, since the overexpression of this factor in choriocarcinoma cells mimics the same transcriptional profile observed in PE [29], [34]. Endoplasmatic reticulum (ER) stress, characterized by the accumulation of unfolded proteins and misfolded proteins within the organelle, interfering with functions of synthesis, post-translational folding and assembly of all secreted and membrane-bound proteins, including hormones, growth factors, and receptors [35], [36], [37]. Loss of homeostasis activates unfolded proteins response, consisting of three main signaling routes: PKR-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6) and inositol-requiring 1 (Ire1). Under normal conditions, these transmembrane proteins become inactive by binding glucose-regulated protein 78 (GRP78 or BiP) to its N terminal. However, consumption of GRP78 (Ca2+–dependent chaperone protein) triggered by accumulation of misfolded proteins promotes dimerization, autophosphorylation and activation of PERK and Ire1. Consequently, activation of PERK favors the phosphorylation of eukaryotic initiation factor 2 subunit a (eIF2a) and translation of activating transcription factor-4 (ATF4), which results in blocking protein translation and reducing accumulation in ER. In Golgi complex, ATF6 is cleaved by the transcription factor responsible for the expression of ER chaperone genes. Splices Xbp1 mRNA (originated from activation of Ire endoribonuclease domain) is responsible for the transcription of genes that regulate degradation of misfolded proteins and ER biogenesis. In intense ER stress, PERK and ATF6 favor CHOP and caspase-4 (proapoptotic proteins) synthesis and apoptosis of the affected cell [35], [38]. Dilatation of ER cistaernae in syncytotrophoblast, greater phosphorylation of eIF2a, reduction of protein synthesis, greater apoptosis and impairment of placentation are some changes triggered by ER stress in PE [35]. A research indicates that the expression of GRP78, PERK, eIF2a, ATF4, CHOP, and caspase-12 mRNA, as well as their respective proteins, were significantly higher in human placentas with early and late-onset PE, compared with normal placentas [38]. In addition to the metabolic pathway disorders in this disease, research has reported that there may be maternal immune tolerance to fetal antigens during intrauterine development. It is assumed that the recognition of fetal antigens by CD4+ T cells and by uterine natural killer [33] cells is fundamental to placental growth. Failures in this process cause miscarriages, impaired placentation, changes in placental perfusion and in the activation of the immune system throughout pregnancy [29]. Particular differences are identified in decidual NK cell (dNK) phenotype in PE. Effective trophoblast invasion is regulated by activation and inhibition of receptors (KIR, CD94/NKG2, ILT families) in dNK cells, which favor interaction with trophoblast HLA Class I molecules (HLA-C/G/E). Evidence shows that the frequency of genotype KIR AA associated with the allele HLA-C with C2 epitope, is higher in pregnancies with impairment of spiral artery remodeling [39], [40]. In addition, dNK cells from women with high resistance index (uterine artery Doppler ultrasound) have lower expression of KIR2DL/S1,3,5 and LILRB1 (ILT-2); in turn, the reduction of LILRB1 stimulates the greater expression of tumor necrosis factor-α (TNF-α) and the lower expression of CXCL10. There is also greater secretion of endostatin, angiogenin and the soluble IL-2 receptor. These changes interfere in the ability of dNK cells to regulate trophoblast invasion and migration [40], [41].