1,720,998 research outputs found
Statins, mevalonate pathway and its intermediate products in placental development and preeclampsia
No full textThe mevalonate pathway synthesizes intermediates and products such as cholesterol and non-sterol isoprenoids that are crucial for cell survival and function. In the human placenta, the prenylation of proteins, rather than cholesterol synthesis, represents the main "metabolic target" of mevalonate metabolism. Major cellular functions depend on isoprenylation including proliferation, migration, metabolism and protein glycosylation that are all crucial for proper development of the embryo and the placenta. Statins are inhibitors of HMG-CoA reductase, the enzyme that catalyzes the reduction of HMG-CoA to mevalonic acid by NADPH. In vitro experiments using human placental explants suggest that statins elicit a detrimental effect on placental growth. However, animal and epidemiologic studies show no increase of fetal malformations after exposure to statins during pregnancy. Moreover, emerging evidence from mouse studies suggest that statins may be useful in preventing serious pregnancy complications like preeclampsia
Defects in lysosomal degradation contribute to impaired fibronectin matrix assembly in preeclampsia
No full textObjectives: The glycoprotein,fibronectin (FN), is a fundamentalcomponent of the extracellular matrix (ECM), driving trophoblast inva-sion and angiogenesis in the developing placenta. These events arecompromised in preeclampsia (PE), a pathology typified by impairedangiogenesis. FN undergoes extensive intracellular processing, from itsdimerization and secretion, to signalling, endocytosis and lysosomaldegradation. To date, the mechanisms controlling FN trafficking anddeposition in PE remain unknown, prompting us to investigate FN ma-trix assembly in the human placenta in physiological and pathologicalconditions.Methods: Placentae were collected fromfirst trimester, preeclamptic(n1⁄417), pre-term (n1⁄414) and term (n1⁄415) pregnancies. Placental mesen-chymal cells (pMCs) were isolated and characterized by FACS. Organelleswere isolated using sucrose density gradients and ultracentrifugation.pMCs were exposed to either cycloheximide (protein synthesis inhibitor),Brefeldin A (ER-Golgi transport inhibitor), or the lysosomal inhibitors,NH4Cl and Bafilomycin. Concanavalin A lectin-binding was used to assessFN glycosylation.Results: FN monomers and dimers accumulated in the Golgi and lyso-somal compartments in PE placentae and in PE pMCs relative to age-matched controls, whileFN1mRNA was unchanged. FN intracellularglycosylation was markedly reduced in PE pMCs, accompanied by aberrantER-Golgi transit and secretion. Assessment of protein half-life by cyclo-heximide revealed distinct impairments in FN matrix turnover in PE, whilein controls, FN was sequentially processed from cell-associated solubledimers to matrix-associated insolublefibrils. Confirming impairments inits clearance, lysosomal inhibition by NH4Cl or Bafilomycin in control pMCsstabilized intracellular FN and attenuated integrin-mediated signalling,while in PE, FN failed to be stabilized and continued to aberrantly signaldownstream.Conclusion: This study highlights profound disruptions in key stages offibronectin matrix assembly in preeclampsia, particularly its depositionand lysosomal degradation. Given the importance of pMC-derived ECM intriggering villous angiogenesis, this work sheds new light on the mecha-nisms contributing to abnormal vascular development in P
Compromised JMJD6 Activity Due to Placental Iron Deficiency Underlies Aberrant Fibronectin Processing in Preeclampsia
No full textInduction of placental macrophage migration inhibitory factor (MIF) by low oxygen environment
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Angiomotin (AMOT) Regulates Trophoblast Migration in the Human Placenta Under Oxygen Dependent JMJD6-Mediated Lysyl Hydroxylation
No full textLipid-endoglin interactions in preeclampsia
No full textPreeclampsia has increased circulating levels of a short form of the auxillary TGF-beta (TGFB) receptor endoglin (sENG). However, its processing, release and functionality in preeclampsia remains poorly understood. Objective: To elucidate whether ENG is attracted to syncytial sphingomyelin-enriched apical membrane subdomains that facilitate ENG cleavage and subsequent shedding of sENG into the maternal circulation in preeclampsia. Results: We show that ENG interacts with specific sphingomyelin(SM)s which promote its clustering with particular metalloproteinases (MMP) in SM-enriched lipid rafts of the apical syncytial membranes from preeclamptic placenta where ENG is cleaved by MMP into sENG. The SM-enriched lipid rafts also contain TGFB receptors (TGFBR1 and TGFBR2), but not soluble fms-like tyrosine kinase 1 (sFLT1), another protein secreted in excess in the circulation of women with preeclampsia. The truncated ENG is then released into the maternal circulation via PLAP/CD63-positive and SM-enriched exosomes together with TGFBR1 and 2. Conclusion: Hypoxia-induced SMs facilitate ENG cleavage in the apical syncytial membrane via MMP and subsequent exosomal release of sENG with TGFBR1 and 2 into the maternal circulation. This TGFB receptor complex could block the vascular effects of TGFB in the circulation of preeclamptic women
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Faulty oxygen sensing disrupts angiomotin function in trophoblast cell migration and predisposes to preeclampsia
No full textHuman placenta development and a successful pregnancy is incumbent upon precise oxygendependent control of trophoblast migration/invasion. Persistent low oxygen leading to failed trophoblast invasion promotes inadequate spiral artery remodeling, a characteristic of preeclampsia. Angiomotin (AMOT) is a multifaceted scaffolding protein involved in cell polarity and migration, yet its upstream regulation and significance in the human placenta remain unknown. Herein, we show that AMOT is primarily expressed in migratory extravillous trophoblast cells (EVTs) of the intermediate and distal anchoring column. Its expression increases after 10 weeks of gestation when oxygen tension rises and EVT migration/invasion peaks. Time-lapse imaging confirmed that the AMOT 80-kDa isoform promotes migration of trophoblastic JEG3 and HTR- 8/SVneo cells. In preeclampsia, however, AMOT expression is decreased and its localization to migratory fetomaternal interface EVTs is disrupted. We demonstrate that Jumonji C domain- containing protein 6 (JMJD6), an oxygen sensor, positively regulates AMOT via oxygen-dependent lysyl hydroxylation. Furthermore, in vitro and ex vivo studies show that transforming growth factor-β (TGF-β) regulates AMOT expression, its interaction with polarity protein PAR6, and its subcellular redistribution from tight junctions to cytoskeleton. Our data reveal an oxygen- and TGF-β-driven migratory function for AMOT in the human placenta, and implicate its deficiency in impaired trophoblast migration that plagues preeclampsia
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