Immunohistochemical localization of pregnancy-associated plasma protein A (PAPP-A) in placentae from normal and pre-eclamptic pregnancies

Dobashi, Kazuyoshi; Ajika, K.; Ohkawa, T.; Okano, Hideko; Okinaga, Shoichi; Arai, Kiyoshi

doi:10.1016/s0143-4004(84)80030-2

Cited by 12 publications

(5 citation statements)

References 17 publications

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“…Early immunohistochemical studies on the cellular localization of PAPP-A were conflicting, likely due to different antisera used and the fact that available polyclonal antibodies to PAPP-A contained antibodies to both PAPP-A and proMBP (13). They demonstrated localization only to the apical surface of the syncytiotrophoblasts of 6-wk placentae, as well as term placentae (1,2,(31)(32)(33), or localization to the syncytiotrophoblast and the extravillous, intermediate (invading) trophoblast (34,35). Subsequent immunofluorescence studies, using proMBP-absorbed anti-PAPP-A polyclonal antibodies, localized immunoreactive PAPP-A to the extravillous trophoblast in the anchoring villi, as well as to the syncytiotrophoblast layer in the floating villi (3).…”

Section: Discussionmentioning

confidence: 99%

Pregnancy-Associated Plasma Protein A Proteolytic Activity Is Associated with the Human Placental Trophoblast Cell Membrane

Sun

Overgaard

Oxvig

et al. 2002

The Journal of Clinical Endocrinology & Metabolism

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Pregnancy-associated plasma protein-A (PAPP-A) is a product of the placenta and decidua and is secreted into the maternal circulation during human pregnancy. It recently has been identified as an IGF binding protein (IGFBP)-4 protease. Presumed functions at the maternal-fetal interface are to proteolyze IGFBP-4 and thus increase IGF bioavailability locally in the placenta, to promote IGF-II-mediated trophoblast invasion into the maternal decidua, and to modulate IGF regulation of steroidogenesis and glucose and amino acid transport in the villous. Herein, we have investigated the possibility that IGFBP-4 proteolysis may occur on the trophoblast cell membrane, presumably to increase local bioavailable IGF for interactions with cognate IGF membrane receptors. Human trophoblasts were cultured, trophoblast plasma membranes were isolated and solubilized, and IGFBP-4 protease activity and PAPP-A immunoreactivity in the solubilized plasma membrane fraction were investigated. IGFBP-4 protease activity was detected in solubilized human trophoblast membranes, resulting in cleavage of recombinant human IGFBP-4 into 18- and 14-kDa fragments, detected by Western immunoblot analysis. This protease activity was dependent on the presence of IGF-II, and its metal ion dependence was demonstrated by inhibition of the protease by the metal chelators, EDTA and EGTA. The presence of PAPP-A in solubilized human trophoblast membranes was demonstrated by Western immunoblotting. Trophoblast membrane PAPP-A had a relative molecular weight of approximately 200 kDa and comigrated on (reducing) SDS-PAGE with recombinant human PAPP-A and PAPP-A secreted into media conditioned by cultured human trophoblasts. IGFBP-4 protease activity was not detected after immunodepletion of PAPP-A from the trophoblast membrane fraction with PAPP-A polyclonal antibodies, suggesting the identity of the membrane-derived IGFBP-4 protease as PAPP-A. Immunocytochemistry revealed PAPP-A on the cell membrane and in the cytoplasm of human trophoblasts in culture. Together, these data demonstrate the presence of an IGF-II- and metal-dependent IGFBP-4 protease activity in human trophoblast plasma membranes, identified as PAPP-A, which is well situated to proteolyze IGFBP-4 at the maternal-placental interface to facilitate IGF action at the villous surface and/or the invading extravillous cytotrophoblast.

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Section: Discussionmentioning

confidence: 99%

Pregnancy-Associated Plasma Protein A Proteolytic Activity Is Associated with the Human Placental Trophoblast Cell Membrane

Sun

Overgaard

Oxvig

et al. 2002

The Journal of Clinical Endocrinology & Metabolism

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“…All three analytes are placental products, and immunohistochemical studies have localized hCG and PP13 to the syncytiotrophoblast [3,17,18] and PAPP-A to the villous cytotrophoblast [19] . In digynic triploidy and trisomies 18 and 13, all three analytes are decreased, whereas in trisomy 21, where free ␤ -hCG is increased and PAPP-A is decreased, PP13 is not significantly altered.…”

Section: Discussionmentioning

confidence: 99%

Maternal Serum Placental Protein 13 at Eleven to Thirteen Weeks in Chromosomally Abnormal Pregnancies

et al. 2010

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Objective: To investigate whether the maternal serum concentration of placental protein 13 (PP13) is altered in chromosomally abnormal pregnancies and to examine the potential value of this placental protein in screening for aneuploidies at 11–13 weeks. Methods: The maternal serum concentration of PP13 at 11–13 weeks was compared in 536 euploid and 134 aneuploid pregnancies (trisomy 21: n = 49; trisomy 18: n = 28; trisomy 13: n = 19; Turner syndrome: n = 28; triploidy: n = 10). Results: Serum PP13, expressed as multiples of the median (MoM) of the euploid group, was not significantly different in trisomy 21 (1.12 MoM) pregnancies, but the levels were decreased in trisomy 18 (0.75 MoM), trisomy 13 (0.65 MoM), Turner syndrome (0.61 MoM) and triploidy (0.19 MoM). In both euploid and aneuploid pregnancies there was a significant association of serum PP13 with both serum pregnancy-associated plasma protein A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG; p < 0.0001 for both). Logistic regression analysis demonstrated that the addition of serum PP13 did not improve the prediction of trisomy 13 and 18 provided by a combination of maternal age, nuchal translucency, and serum free β-hCG and PAPP-A. Conclusion: The measurement of maternal serum PP13 at 11–13 weeks does not improve the performance of screening for aneuploidies achieved by current algorithms.

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“…In addition, immunohistochemical studies with first trimester and term placentae have also localized PAPP-A to syncytiotrophoblasts, extravillous trophoblasts, and the extracellular matrix in placental septae (19,39). They demonstrated localization only to the apical surface of the syncytiotrophoblasts of early (6 wk gestation) as well as late (term) placentae (15, 40 -42) or localization to the syncytiotrophoblast and the extravillous, intermediate (invading) trophoblast (43,44). They demonstrated localization only to the apical surface of the syncytiotrophoblasts of early (6 wk gestation) as well as late (term) placentae (15, 40 -42) or localization to the syncytiotrophoblast and the extravillous, intermediate (invading) trophoblast (43,44).…”

Section: Discussionmentioning

confidence: 99%

Identification and Regulation of the IGFBP-4 Protease and Its Physiological Inhibitor in Human Trophoblasts and Endometrial Stroma: Evidence for Paracrine Regulation of IGF-II Bioavailability in the Placental Bed during Human Implantation

Giudice

Conover

Bale

et al. 2002

The Journal of Clinical Endocrinology &Amp; Metabolism

109

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The IGF family plays an important role in implantation and placental physiology. IGF-II is abundantly expressed by placental trophoblasts, and IGF binding protein (IGFBP)-4, a potent inhibitor of IGF actions, is the second most abundant IGFBP in the placental bed, expressed exclusively by the maternal decidua. Proteolysis of IGFBP-4 results in decreased affinity for IGF peptides, thereby enhancing IGF actions. In the current study, we have identified the IGFBP-4 protease and its inhibitor in human trophoblast and decidualized endometrial stromal cell cultures, and we have investigated their regulation in an effort to understand control of IGF-II bioavailability at the placental-decidual interface in human implantation. IGFBP-4 protease activity was detected in conditioned media (CM) from human trophoblasts and decidualized endometrial stromal cells using (125)I-IGFBP-4 substrate. Identification of the IGFBP-4 protease as pregnancy-associated plasma protein-A (PAPP-A) was confirmed by specific immunoinhibition and immunodepletion of the IGFBP-4 protease activity with specific PAPP-A antibodies. The IGFBP-4 protease activity was IGF-II-dependent in trophoblast CM. In decidualized stromal CM, PAPP-A/IGFBP-4 protease activity was also IGF-II-dependent, but was evident only when IGF-II was added in molar excess of the predominant IGFBP in decidualized stromal cell CM, IGFBP-1, supporting bioavailable IGF-II as a key cofactor of IGFBP-4 proteolysis by PAPP-A. Cultured first and second trimester human trophoblasts (n = 5) secreted PAPP-A into CM with mean +/- SEM levels of 172.4 +/- 32.8 mIU/liter.10(5) cells, determined by specific ELISA. PAPP-A in trophoblast CM (n = 3) and did not change in the presence of IGF-II (1-100 ng/ml). Cultured human endometrial stromal cells (n = 4) secreted low levels of PAPP-A (6.25 +/- 3.6 mIU/liter.10(5) cells). A physiological inhibitor of PAPP-A, the proform of eosinophil major basic protein (proMBP), was detected in trophoblast CM at levels of 1853 +/- 308 mIU/liter.10(5) cells, determined by specific ELISA, and was nearly undetectable in CM of human endometrial stromal cells. Upon in vitro decidualization of endometrial stromal cells with progesterone, PAPP-A levels in CM increased nearly 9-fold without a concomitant change in proMBP. In contrast to the experiments with trophoblasts, IGF-II and the IGF analogues, Leu(27) IGF-II, and Des (1-6) IGF-II, resulted in a dose-dependent decrease of PAPP-A levels in decidualized endometrial stromal CM by 70-90%, and a dose-dependent increase in proMBP of 14- to 41-fold. The data demonstrate conclusively that the IGF-II-dependent IGFBP-4 protease of human trophoblast and decidual origin is PAPP-A. Furthermore, the differential regulation of decidual PAPP-A and proMBP by insulin-like peptides supports a role for trophoblast-derived IGF-II as a paracrine regulator of these maternal decidual products that have the potential to regulate IGF-II bioavailability at the trophoblast-decidual interface. Overall, the data underscore potential roles for ...

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Immunohistochemical localization of pregnancy-associated plasma protein A (PAPP-A) in placentae from normal and pre-eclamptic pregnancies

Cited by 12 publications

References 17 publications

Pregnancy-Associated Plasma Protein A Proteolytic Activity Is Associated with the Human Placental Trophoblast Cell Membrane

Pregnancy-Associated Plasma Protein A Proteolytic Activity Is Associated with the Human Placental Trophoblast Cell Membrane

Maternal Serum Placental Protein 13 at Eleven to Thirteen Weeks in Chromosomally Abnormal Pregnancies

Identification and Regulation of the IGFBP-4 Protease and Its Physiological Inhibitor in Human Trophoblasts and Endometrial Stroma: Evidence for Paracrine Regulation of IGF-II Bioavailability in the Placental Bed during Human Implantation

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