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

Macintire, Kate; Tuohey, Laura; Ye, Louie; Palmer, Kirsten; Gantier, Michael P.; Tong, Stephen; Kaitu’u-Lino, Tu’uhevaha J

doi:10.1071/rd12384

Cited by 43 publications

(40 citation statements)

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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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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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“…Previous work reported that abnormal expression of PAPPA2 was associated with pregnancy complications (Buimer et al, 2008;Crosley et al, 2014a;Macintire et al, 2014;Munnangi et al, 2014). Circulating PAPPA2 was recommend as a valuable marker to screen early onset severe PE (Crosley et al, 2014b;Macintire et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Circulating PAPPA2 was recommend as a valuable marker to screen early onset severe PE (Crosley et al, 2014b;Macintire et al, 2014). PE is typically characterized by insufficient EVT differentiation and inadequate maternal environment remodeling (Lyall et al, 2013) due to the impaired invasion and migration ability of EVT.…”

Section: Discussionmentioning

confidence: 99%

“…The abnormal expression of PAPPA2 in pregnancy complications have been reported (Buimer et al, 2008;Macintire et al, 2014;Munnangi et al, 2014). It has been suggested that PAPPA2 could be an important marker for early onset preeclampsia (PE) (Macintire et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…It has been suggested that PAPPA2 could be an important marker for early onset preeclampsia (PE) (Macintire et al, 2014). Mice models have been established to explore the exact role of PAPPA2 during placentation (Conover et al, 2011) but no obvious placenta defects were reported.…”

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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A map of human circular RNAs in clinically relevant tissues

et al. 2017

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Cellular circular RNAs (circRNAs) are generated by head-to-tail splicing and are present in all multicellular organisms studied so far. Recently, circRNAs have emerged as a large class of RNA which can function as post-transcriptional regulators. It has also been shown that many circRNAs are tissue- and stage-specifically expressed. Moreover, the unusual stability and expression specificity make circRNAs important candidates for clinical biomarker research. Here, we present a circRNA expression resource of 20 human tissues highly relevant to disease-related research: vascular smooth muscle cells (VSMCs), human umbilical vein cells (HUVECs), artery endothelial cells (HUAECs), atrium, vena cava, neutrophils, platelets, cerebral cortex, placenta, and samples from mesenchymal stem cell differentiation. In eight different samples from a single donor, we found highly tissue-specific circRNA expression. Circular-to-linear RNA ratios revealed that many circRNAs were expressed higher than their linear host transcripts. Among the 71 validated circRNAs, we noticed potential biomarkers. In adenosine deaminase-deficient, severe combined immunodeficiency (ADA-SCID) patients and in Wiskott-Aldrich-Syndrome (WAS) patients’ samples, we found evidence for differential circRNA expression of genes that are involved in the molecular pathogenesis of both phenotypes. Our findings underscore the need to assess circRNAs in mechanisms of human disease.Key messages circRNA resource catalog of 20 clinically relevant tissues.circRNA expression is highly tissue-specific.circRNA transcripts are often more abundant than their linear host RNAs.circRNAs can be differentially expressed in disease-associated genes. Electronic supplementary materialThe online version of this article (10.1007/s00109-017-1582-9) contains supplementary material, which is available to authorized users.

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

Cited by 43 publications

References 26 publications

Interleukin-11 alters placentation and causes preeclampsia features in mice

Interleukin-11 alters placentation and causes preeclampsia features in mice

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

A map of human circular RNAs in clinically relevant tissues

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