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Villous trophoblast apoptosis is elevated and restricted to cytotrophoblasts in pregnancies complicated by preeclampsia, IUGR, or preeclampsia with IUGR.

ABSTRACT: Human placental villi are surfaced by an outer multinucleated syncytiotrophoblast and underlying mononucleated cytotrophoblasts. Conflicting data have attributed one, or the other, of these villous trophoblast phenotypes to undergo enhanced apoptosis in complicated pregnancies, compared to term, normotensive pregnancies. We use high-resolution confocal microscopy after co-staining for E-cadherin, as a trophoblast plasma membrane marker, and for the cleavage products of cytokeratin 18 and PARP1, as markers for caspase-mediated apoptosis, to distinguish between apoptotic cytotrophoblasts and apoptosis within the syncytiotrophoblast. We test the hypothesis that increased caspase-mediated apoptosis occurs in villi of placentas derived from pregnancies complicated by preeclampsia, intrauterine growth restriction (IUGR), or both. We find significantly elevated apoptosis in villous cytotrophoblasts from women with preeclampsia and/or IUGR, compared to term, normotensive pregnancies. Apoptosis of cytotrophoblasts in villi from complicated pregnancies appears to progress similarly to what we found previously for apoptotic cytotrophoblasts in villi from in term, normotensive pregnancies. Notably, caspase-mediated apoptosis was not detectable in regions with intact syncytiotrophoblast, suggesting strong repression of apoptosis in this trophoblast phenotype in vivo. We suggest that the elevated apoptosis in cytotrophoblasts in preeclampsia contributes to the placental dysfunction characteristic of this disorder. We also propose that repression of apoptosis in the syncytiotrophoblast is important to prevent apoptosis sweeping throughout the syncytium, which would result in widespread death of this essential interface for maternal-fetal exchange.

SUBMITTER: Longtine MS

PROVIDER: S-EPMC3467099 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Villous trophoblast apoptosis is elevated and restricted to cytotrophoblasts in pregnancies complicated by preeclampsia, IUGR, or preeclampsia with IUGR.

Longtine M S MS Chen B B Odibo A O AO Zhong Y Y Nelson D M DM

Placenta 20120216 5

Human placental villi are surfaced by an outer multinucleated syncytiotrophoblast and underlying mononucleated cytotrophoblasts. Conflicting data have attributed one, or the other, of these villous trophoblast phenotypes to undergo enhanced apoptosis in complicated pregnancies, compared to term, normotensive pregnancies. We use high-resolution confocal microscopy after co-staining for E-cadherin, as a trophoblast plasma membrane marker, and for the cleavage products of cytokeratin 18 and PARP1, ...[more]

PMID: 22341340

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Project description:IntroductionPreeclampsia is associated with maternal metabolic disturbances, but longitudinal studies with comprehensive metabolic profiling are lacking. We aimed to determine metabolic profiles across gestation in women who developed preeclampsia compared with women with healthy pregnancies. We also explored the respective effects of body mass index (BMI) and preeclampsia on various metabolic measures.Material and methodsWe measured 91 metabolites by high-throughput nuclear magnetic resonance spectroscopy at four time points (visits) during pregnancy (weeks 14-16, 22-24, 30-32 and 36-38). Samples were taken from a Norwegian pregnancy cohort. We fitted a linear regression model for each metabolic measure to compare women who developed preeclampsia (n = 38) and healthy controls (n = 70).ResultsAmong women who developed preeclampsia, 92% gave birth after 34 weeks of gestation. Compared to women with healthy pregnancies, women who developed preeclampsia had higher levels of several lipid-related metabolites at visit 1, whereas fewer differences were observed at visit 2. At visit 3, the pattern from visit 1 reappeared. At visit 4 the differences were larger in most subgroups of very-low-density lipoprotein particles, the smallest high-density lipoprotein, total lipids and triglycerides. Total fatty acids were also increased, of which monounsaturated fatty acids and saturated fatty acids showed more pronounced differences. Concentration of glycine tended to be lower in pregnancies with preeclampsia until visit 3, although this was not significant after correction for multiple testing. After adjustment for age, BMI, parity and gestational weight gain, all significant differences were attenuated at visits 1 and 2. The estimates were less affected by adjustment at visits 3 and 4.ConclusionsIn early pregnancy, the metabolic differences between preeclamptic and healthy pregnancies were primarily driven by maternal BMI, probably representing the women's pre-pregnancy metabolic status. In early third trimester, several weeks before clinical manifestation, the differences were less influenced by BMI, indicating preeclampsia-specific changes. Near term, women with preeclampsia developed an atherogenic metabolic profile, including elevated total lipids, very-low-density lipoprotein, triglycerides, and total fatty acids.

Project description:Excessive accumulation of misfolded proteins was recently demonstrated in preeclampsia. We examined levels and activity of circulatory proteasome and immunoproteasome (inflammatory subtype) in preeclampsia and hemolysis, elevated liver enzymes, and thrombocytopenia (HELLP) syndrome. We analyzed samples from women with hypertensive pregnancy disorders (n=115), including preeclampsia with severe features (sPE) and HELLP syndrome, and normotensive controls (n=45). Plasma proteasome and immunoproteasome immunoreactivity were determined by quantifying the α-subunit of the 20S core and β5i (proteasome subunit beta 8 [PSMB8]), respectively. Plasma proteasome activity was analyzed with fluorogenic substrates. MG132, lactacystin, and ONX0914 were used to inhibit the circulating proteasome and immunoproteasome, respectively. Plasma cytokine profiles were evaluated by multiplex immunoassay. Placental expression of β5 (constitutive proteasome) and β5i (immunoproteasome) was interrogated by immunohistochemistry. Women with sPE had increased plasma 20S levels ( P<0.001) and elevated lytic activities (chymotrypsin-like 7-fold, caspase-like 4.2-fold, trypsin-like 2.2-fold; P <0.001 for all) compared with pregnant controls. Women with features of HELLP displayed the highest plasma proteasome levels and activity, which correlated with decreased IFN-γ (interferon-γ), and increased IL (interleukin)-8 and IL-10. In sPE and HELLP, chymotrypsin-like activity was suppressed by proteasome inhibitors including ONX0914. Compared with gestational age-matched controls, sPE placentas harbored increased β5 and β5i immunostaining in trophoblasts. β5i signal was elevated in HELLP with predominant staining in villous core, extravillous trophoblasts in placental islands, and extracellular vesicles in intervillous spaces. Pregnancy represents a state of increased proteostatic stress. sPE and HELLP were characterized by significant upregulation in circulating levels and lytic activity of the proteasome that was partially explained by placental immunoproteasome upregulation.

Dataset Information

Villous trophoblast apoptosis is elevated and restricted to cytotrophoblasts in pregnancies complicated by preeclampsia, IUGR, or preeclampsia with IUGR.

Publications

Villous trophoblast apoptosis is elevated and restricted to cytotrophoblasts in pregnancies complicated by preeclampsia, IUGR, or preeclampsia with IUGR.

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