Expression of pregnancy-associated plasma protein A2 during pregnancy in human and mouse

Wang, Joyce; Qiu, Qing; Haider, Maliha; Bell, Michael D.; Gruslin, Andrée; Christians, Julian K.

doi:10.1677/joe-09-0136

Cited by 53 publications

(56 citation statements)

References 44 publications

(61 reference statements)

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“…It is also the first time that the decreasing expression of PAPPA2 in human placenta along the gestational period was demonstrated. Our observation was different from the report of Wang et al (2009), who found that the PAPPA2 level was increased in maternal circulation along the gestational period (Wang et al, 2009). Thus, it is reasonable to deduce that the maternal circulatory PAPPA2 in the second and third trimester does not originate from the placenta but actually from the maternal body.…”

Section: Discussioncontrasting

confidence: 99%

“…Furthermore, many factors involved in facilitating trophoblast physiological function have also been revealed (Das et al, 2002). Those gene products include proteases (Wang et al, 2009), growth factors and their receptors (Morrish et al, 2007), cytokines (Das et al, 2002), and proteins involved in maintaining cell structures (Cronier et al, 2002). Normal trophoblast lineage and placentation under the regulation of necessary genes, which undergo intrinsic spatial and temporal expression, is the prerequisite for successful pregnancy.…”

Section: Introductionmentioning

confidence: 99%

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Expression of PAPPA2 in human fetomaternal interface and involvement in trophoblast invasion and migration

2016

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ABSTRACT. Pregnancy-associated plasma protein-A 2 (PAPPA2) is a placental-enriched gene that is important for normal human placentation and defects in the gene can cause complications in pregnancy. Yet the exact expression pattern and role of PAPPA2 in the human fetomaternal interface are not clear. In this study, in situ hybridization (ISH) and immunohistochemistry (IHC) were employed to examine the spatial and temporal expression of PAPPA2 in the human fetomaternal interface. IHC results exhibited wide expression of PAPPA2 in the fetomaternal interface, with placental syncytiatrophoblast (STB) and extravillous trophoblast (EVT) showing strong expression and the cytotrophoblast (CTB) showing weak expression of PAPPA2. These results were confirmed by ISH. Quantitative reverse transcription- polymerase chain reaction and western blot showed the elevation of PAPPA2 in first trimester EVT differentiation and term CTB spontaneous syncytialization. PAPPA2-siRNA transfection significantly depressed the invasion and migration ability of a trophoblast cell line (HTR8/SVneo) in a transwell migration and Matrigel invasion model compared to a negative control siRNA (P < 0.05), also revealing that matrix metalloproteinase 9 (MMP9) secretion is downregulated. This was confirmed using a human first trimester placental villi explant culture model. Our results reveal the spatial and temporal expression of PAPPA2 in the human fetomaternal interface and show the positive regulatory role of PAPPA2 in human trophoblast invasion and migration through the secretion of MMP9.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression of PAPPA2 in human fetomaternal interface and involvement in trophoblast invasion and migration

2016

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“…However, the present study appears to be the first to comprehensively compare PAPPA2 immunohistochemistry between PT, PE and term samples and to observe a lack of staining in term samples. Although variable, placental PAPPA2 mRNA levels have also been reported to decline with gestation (Winn et al 2009) and PAPPA2 has been shown to be a cleavage protease for insulin-like growth factor (IGF) binding protein 5 (Wang et al 2009) bioavailability. Thus, the decline in placental PAPPA2 protein observed at term in our immunohistochemical samples is possibly a result of the decreased placental growth occurring during this phase of pregnancy.…”

Section: Discussionmentioning

confidence: 99%

PAPPA2 is increased in severe early onset pre-eclampsia and upregulated with hypoxia

Macintire

Tuohey

et al. 2014

Reprod. Fertil. Dev.

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Abstract. Severe early onset pre-eclampsia is a serious pregnancy complication, believed to arise as a result of persistent placental hypoxia due to impaired placentation. Pregnancy-associated plasma protein A2 (PAPPA2) is very highly expressed in the placenta relative to all other tissues. There is some evidence that PAPPA2 mRNA and protein are increased in association with pre-eclampsia. The aim of the present study was to characterise the mRNA and protein expression, as well as localisation, of PAPPA2 in an independent cohort of severe early onset pre-eclamptic placentas. We also examined whether exposing placental explants to hypoxia (1% oxygen) changed the expression of PAPPA2. Expression of PAPPA2 mRNA and protein was upregulated in severe early onset pre-eclamptic placentas compared with preterm controls and localised to the syncytiotrophoblast. Interestingly, protein localisation was markedly reduced in term placenta. Syncytialisation of BeWo cells did not change PAPPA2 expression. However, hypoxia upregulated PAPPA2 mRNA and protein expression in primary placental explants. Together, our data suggest that PAPPA2 may be upregulated in severe pre-eclampsia and, functionally, this may be mediated via increased placental hypoxia known to occur with this pregnancy disorder.

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“…Pregnancy-associated plasma protein A2 (PAPPA2) was up-regulated 2.6-fold (P < 0.001). PAPPA2 protein is elevated in EO PE placenta (24) and maternal serum before PE onset (25) and expressed by first-trimester EVT in women and by invasive trophoblasts in mice (26). However, the functional role of PAPPA2 in EVT invasion is not known.…”

Section: Il11 Impedes Human Evt Invasion Via the Pregnancy-associatedmentioning

confidence: 99%

Interleukin-11 alters placentation and causes preeclampsia features in mice

Winship

Koga

Menkhorst

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Preeclampsia (PE) is a pregnancy-specific disorder characterized by hypertension and proteinuria after 20 wk gestation. Abnormal extravillous trophoblast (EVT) invasion and remodeling of uterine spiral arterioles is thought to contribute to PE development. Interleukin-11 (IL11) impedes human EVT invasion in vitro and is elevated in PE decidua in women. We demonstrate that IL11 administered to mice causes development of PE features. Immunohistochemistry shows IL11 compromises trophoblast invasion, spiral artery remodeling, and placentation, leading to increased systolic blood pressure (SBP), proteinuria, and intrauterine growth restriction, although nonpregnant mice were unaffected. Real-time PCR array analysis identified pregnancy-associated plasma protein A2 (PAPPA2), associated with PE in women, as an IL11 regulated target. IL11 increased PAPPA2 serum and placental tissue levels in mice. In vitro, IL11 compromised primary human EVT invasion, whereas siRNA knockdown of PAPPA2 alleviated the effect. Genes regulating uterine natural killer (uNK) recruitment and differentiation were down-regulated and uNK cells were reduced after IL11 treatment in mice. IL11 withdrawal in mice at onset of PE features reduced SBP and proteinuria to control levels and alleviated placental labyrinth defects. In women, placental IL11 immunostaining levels increased in PE pregnancies and in serum collected from women before development of early-onset PE, shown by ELISA. These results indicate that elevated IL11 levels result in physiological changes at the maternal-fetal interface, contribute to abnormal placentation, and lead to the development of PE. Targeting placental IL11 may provide a new treatment option for PE.placenta | trophoblast | cytokines | pregnancy P reeclampsia (PE) is a pregnancy-induced disorder characterized by hypertension and proteinuria, unique to humans, affecting ∼8% of pregnancies (1). The etiology is poorly understood (2); nevertheless, there is substantial evidence showing abnormal placentation is the key underlying cause. During pregnancy, highly invasive extravillous trophoblasts (EVT) acquire vascular-like properties to remodel uterine spiral arterioles. This creates low-resistance, large-diameter vessels that promote uteroplacental blood supply to sustain fetal growth (3, 4). It is widely accepted that inadequate trophoblast invasion and impaired uterine spiral artery remodeling is an initiating factor in the development of PE (5). This is thought to impair uteroplacental arterial flow and lead to placental oxidative stress (6). PE is associated with increased placental secretion of proinflammatory cytokines (7) and angiogenic regulators (8), thought to contribute to widespread maternal endothelial dysfunction. The clinical symptoms of PE are hypertension, proteinuria, and peripheral and/or cerebral edema. Symptoms can differentially manifest during the second (early-onset, EO), or third (late-onset, LO) trimester (9). In addition to the maternal symptoms, PE is also frequently associated with prematurit...

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Expression of pregnancy-associated plasma protein A2 during pregnancy in human and mouse

Cited by 53 publications

References 44 publications

Expression of PAPPA2 in human fetomaternal interface and involvement in trophoblast invasion and migration

Expression of PAPPA2 in human fetomaternal interface and involvement in trophoblast invasion and migration

PAPPA2 is increased in severe early onset pre-eclampsia and upregulated with hypoxia

Interleukin-11 alters placentation and causes preeclampsia features in mice

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