First-Trimester Levels of Pregnancy-Associated Plasma Protein A2 (PAPP-A2) in the Maternal Circulation Are Elevated in Pregnancies That Subsequently Develop Preeclampsia

Crosley, Erin; Durland, Ursula; Seethram, Ken; MacRae, George S.; Gruslin, Andrée; Christians, Julian K.

doi:10.1177/1933719113512532

Cited by 28 publications

(26 citation statements)

References 42 publications

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“…Given the report of PAPP-A2 elevation in the first trimester in women who subsequently develop preeclampsia [5], the elevation of PAPP-A2 by the early third trimester in the sera and placentas of women with preeclampsia, and the on-off-on again developmental expression pattern of PAPP-A2, the question remains as to whether in preeclampsia PAPP-A2 expression is not appropriately downregulated in the second trimester. If in early pregnancy, PAPP-A2 cleaves IGFBP5, releasing IGF to potentiate cytotrophoblast migration and invasion, then the persistent elevation may reflect an attempt to further stimulate invasion when in normal development this is no longer required.…”

Section: Discussionmentioning

confidence: 99%

“…Extravillous trophoblast invasion is stimulated by insulin growth factors (IGFs) whose bioavailability is regulated by insulin-like binding proteins (IGFBPs) [5-8]. Pregnancy-associated plasma protein-A2 (PAPP-A2), is an insulin-like growth factor-binding protein protease, whose natural substrate is IGFBP-5, and to a lesser extent, IGFBP-3 [9].…”

Section: Introductionmentioning

confidence: 99%

“…RNA and protein studies confirm increased levels of PAPP-A2 in both placenta and maternal serum of preeclamptic subjects compared with controls [11, 20, 21], as well as up-regulated in HELLP syndrome [22], and fetal growth restriction [19]. Recently, first trimester PAPP-A2 levels were reported to be elevated in pregnancies that subsequently developed preeclampsia [5]. However, less is known about PAPP-A2 expression over gestation in normal pregnancy and in response to labor, particularly within the different regions of the placenta, specifically the basal plate (area of trophoblast invasion) and chorionic villi (area of exchange between maternal and fetal compartments).…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of human placental PAPP-A2 over gestation and in preeclampsia

2016

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Introduction Pregnancy Associated Plasma Protein A2 (PAPP-A2) is a pregnancy related insulin-like growth factor binding protein-5 (IGFBP-5) protease, known to be elevated in preeclampsia. As the insulin-like growth factors are important in human implantation and placentation, we sought to determine the expression pattern of PAPP-A2 over human gestation in normal and preeclamptic pregnancies to evaluate its role in placental development and the pathogenesis of preeclampsia. Methods Placental basal plate and chorionic villi samples, maternal and fetal cord blood sera were obtained from preeclamptic and control pregnancies. Formalin-fixed tissue sections from across gestation were stained for cytokeratin-7, HLA-G, and PAPP-A2. PAPP-A2 immunoblot analysis was also performed on protein lysates and sera. Results PAPP-A2 expression is predominately expressed by differentiated trophoblasts and fetal endothelium. Chorionic villi show strong expression in the first trimester, followed by a progressive decrease in the second trimester, which returns in the third trimester. PAPP-A2 expression is not impacted by labor. PAPP-A2 is increased in the basal plate, chorionic villi and maternal sera in preeclampsia compared to controls, but is not detectable in cord blood. Discussion PAPP-A2 is differentially expressed in different trophoblast populations and shows strong down regulation in the mid second trimester in chorionic villous samples. Both maternal sera and placental tissue from pregnancies complicated by preeclampsia show increased levels of PAPP-A2. PAPP-A2 levels are not altered by labor. Additionally, PAPP-A2 cannot be detected in cord blood demonstrating that the alterations in maternal and placental PAPP-A2 are not recapitulated in the fetal circulation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential expression of human placental PAPP-A2 over gestation and in preeclampsia

2016

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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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“…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%

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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First-Trimester Levels of Pregnancy-Associated Plasma Protein A2 (PAPP-A2) in the Maternal Circulation Are Elevated in Pregnancies That Subsequently Develop Preeclampsia

Cited by 28 publications

References 42 publications

Differential expression of human placental PAPP-A2 over gestation and in preeclampsia

Differential expression of human placental PAPP-A2 over gestation and in preeclampsia

Interleukin-11 alters placentation and causes preeclampsia features in mice

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

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