Increased levels of pregnancy-associated plasma protein-A2 in the serum of pre-eclamptic patients

Nishizawa, Haruki; Pryor-Koishi, Kanako; Suzuki, Manami; Kato, Takema; Kogo, Hiroshi; Sekiya, Takao; Kurahashi, Hiroki; Udagawa, Yasuhiro

doi:10.1093/molehr/gan054

Cited by 67 publications

(92 citation statements)

References 26 publications

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“…Several previous studies have published data indicating that PAPPA2 is increased in PE (Buimer et al 2008;Sitras et al 2009;Várkonyi et al 2010;Wagner and Christians 2010). In addition, PAPPA2 has also been localised to the syncytiotrophoblast previously (Nishizawa et al 2008;Wagner and Christians 2010) in both PE and PT placentas.…”

Section: Discussionmentioning

confidence: 87%

“…Nishizawa et al (2008) previously assessed PAPPA2 immunohistochemistry in term control (but not preterm) and severe early onset PE placentas and also suggested a decrease in PAPPA2 in control samples compared with PE. 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.…”

Section: Discussionmentioning

confidence: 99%

“…The collective cohort size in all reports demonstrating PAPPA2 protein is increased in severe preterm PE has thus far been limited to only 30 (Nishizawa et al 2008;Winn et al 2009). Therefore, we thought it was important to provide independent confirmation of this finding.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, recent reports demonstrate a link between PAPPA2 and PE (Nishizawa et al 2008;Winn et al 2009;Paiva et al 2011). However, the evidence showing raised PAPPA2 protein in severe preterm PE (responsible for most of the morbidity caused by this disease) is limited to 30 cases described to date (Nishizawa et al 2008;Winn et al 2009). Thus, this association merits further independent validation.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…Unlike PAPPA, which proteolyses both IGFBP4 and IGFBP5 (Boldt et al 2004), PAPPA2 cleaves IGFBP5 and may also show lower proteolytic activity against IGFBP3 (Overgaard et al 2001). Although the physiological functions of PAPPA2 have not been studied, at least four recent studies have found PAPPA2 to be upregulated in hypertensive disorders of pregnancy including preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome (Buimer et al 2008, Nishizawa et al 2008, Sitras et al 2009, Winn et al 2009.…”

Section: Introductionmentioning

confidence: 99%

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

Wang¹,

Qiu²,

Haider³

et al. 2009

Journal of Endocrinology

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Pregnancy-associated plasma protein-A and -A2 (PAPPA and PAPPA2) are proteases that cleave IGF binding proteins (IGFBPs) and thereby increase the bioavailability of growth factors. PAPPA has long been recognized as a marker of fetal genetic disorders and adverse pregnancy outcomes. In contrast, although PAPPA2 is also highly expressed in human placenta, its physiological importance is not clear. To establish whether mice will be a useful model for the study of PAPPA2, we compared the patterns of expression of PAPPA2 in the placentae of mouse and human. We show, for the first time, that Pappa2 is highly expressed in mouse placenta, as is the case in humans. Specifically, it is expressed at the interface of the maternal and fetal layers of the mouse placenta at all gestational stages studied (10 . [5][6][7][8][9][10][11][12][13][14][15][16] . 5 days post coitum).Similarly, PAPPA2 is expressed in the syncytiotrophoblast layer of human placental villi and is also detected in some invasive extravillous trophoblasts in the first trimester. These results are consistent with a model whereby PAPPA2 cleaves IGFBPs produced in the maternal decidua to promote fetoplacental growth, and indicate that this protein may play analogous roles in human and mouse placenta. PAPPA2 protein is detectable in the circulation of pregnant mice and humans during the first trimester and at term, raising the possibility that PAPPA2 may be a useful biomarker of placental dysfunction. Pappa2 expression also shows specific localization within the mouse embryo and therefore may play roles in fetal development, independent of its action in the placenta.

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Whole transcriptome profiling of placental pathobiology in SARS‐CoV‐2 pregnancies identifies placental dysfunction signatures

Stylianou,

Sebina,

Matigian

et al. 2024

Clin & Trans Imm

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ObjectivesSevere Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) virus infection in pregnancy is associated with higher incidence of placental dysfunction, referred to by a few studies as a ‘preeclampsia‐like syndrome’. However, the mechanisms underpinning SARS‐CoV‐2‐induced placental malfunction are still unclear. Here, we investigated whether the transcriptional architecture of the placenta is altered in response to SARS‐CoV‐2 infection.MethodsWe utilised whole‐transcriptome, digital spatial profiling, to examine gene expression patterns in placental tissues from participants who contracted SARS‐CoV‐2 in the third trimester of their pregnancy (n = 7) and those collected prior to the start of the coronavirus disease 2019 (COVID‐19) pandemic (n = 9).ResultsThrough comprehensive spatial transcriptomic analyses of the trophoblast and villous core stromal cell subpopulations in the placenta, we identified SARS‐CoV‐2 to promote signatures associated with hypoxia and placental dysfunction. Notably, genes associated with vasodilation (NOS3), oxidative stress (GDF15, CRH) and preeclampsia (FLT1, EGFR, KISS1, PAPPA2) were enriched with SARS‐CoV‐2. Pathways related to increased nutrient uptake, vascular tension, hypertension and inflammation were also enriched in SARS‐CoV‐2 samples compared to uninfected controls.ConclusionsOur findings demonstrate the utility of spatially resolved transcriptomic analysis in defining the underlying pathogenic mechanisms of SARS‐CoV‐2 in pregnancy, particularly its role in placental dysfunction. Furthermore, this study highlights the significance of digital spatial profiling in mapping the intricate crosstalk between trophoblasts and villous core stromal cells, thus shedding light on pathways associated with placental dysfunction in pregnancies with SARS‐CoV‐2 infection.

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Increased levels of pregnancy-associated plasma protein-A2 in the serum of pre-eclamptic patients

Cited by 67 publications

References 26 publications

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

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

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

Whole transcriptome profiling of placental pathobiology in SARS‐CoV‐2 pregnancies identifies placental dysfunction signatures

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