Placental Apoptosis in Health and Disease
Andrew N. Sharp
Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK
Search for more papers by this authorAlexander E.P. Heazell
Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK
Search for more papers by this authorIan P. Crocker
Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK
Search for more papers by this authorGil Mor
Department of Obstetrics Gynecology & Reproductive Science, Reproductive Immunology Unit, Yale University, New Heaven, CT, USA
Search for more papers by this authorAndrew N. Sharp
Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK
Search for more papers by this authorAlexander E.P. Heazell
Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK
Search for more papers by this authorIan P. Crocker
Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK
Search for more papers by this authorGil Mor
Department of Obstetrics Gynecology & Reproductive Science, Reproductive Immunology Unit, Yale University, New Heaven, CT, USA
Search for more papers by this authorE-mail: [email protected]
Abstract
Citation Sharp AN, Heazell AEP, Crocker IP, Mor G. Placental apoptosis in health and disease. Am J Reprod Immunol 2010; 64: 159–169
Apoptosis, programmed cell death, is an essential feature of normal placental development but is exaggerated in association with placental disease. Placental development relies upon effective implantation and invasion of the maternal decidua by the placental trophoblast. In normal pregnancy, trophoblast apoptosis increases with placental growth and advancing gestation. However, apoptosis is notably exaggerated in the pregnancy complications, hydatidiform mole, pre-eclampsia, and intrauterine growth restriction (IUGR). Placental apoptosis may be initiated by a variety of stimuli, including hypoxia and oxidative stress. In common with other cell-types, trophoblast apoptosis follows the extrinsic or intrinsic pathways culminating in the activation of caspases. In contrast, the formation of apoptotic bodies is less clearly identified, but postulated by some to involve the clustering of apoptotic nuclei and liberation of this material into the maternal circulation. In addition to promoting a favorable maternal immune response, the release of this placental-derived material is thought to provoke the endothelial dysfunction of pre-eclampsia. Widespread apoptosis of the syncytiotrophoblast may also impair trophoblast function leading to the reduction in nutrient transport seen in IUGR. A clearer understanding of placental apoptosis and its regulation may provide new insights into placental pathologies, potentially suggesting therapeutic targets.
References
- 1 Kerr JF, Wyllie AH, Currie AR: Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239–257.
- 2 Lazebnik YA, Cole S, Cooke CA, Nelson WG, Earnshaw WC: Nuclear events of apoptosis in vitro in cell-free mitotic extracts: a model system for analysis of the active phase of apoptosis. J Cell Biol 1993; 123: 7–22.
- 3 Arends MJ, Wyllie AH: Apoptosis: mechanisms and roles in pathology. Int Rev Exp Pathol 1991; 32: 223–254.
- 4 Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM: Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 1992; 148: 2207–2216.
- 5 Straszewski-Chavez SL, Abrahams VM, Mor G: The role of apoptosis in the regulation of trophoblast survival and differentiation during pregnancy. Endocr Rev 2005; 26: 877–897.
- 6 Chinnaiyan AM, Tepper CG, Seldin MF, O’Rourke K, Kischkel FC, Hellbardt S, Krammer PH, Peter ME, Dixit VM: FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis. J Biol Chem 1996; 271: 4961–4965.
- 7 Varfolomeev EE, Boldin MP, Goncharov TM, Wallach D: A potential mechanism of “cross-talk” between the p55 tumor necrosis factor receptor and Fas/APO1: proteins binding to the death domains of the two receptors also bind to each other. J Exp Med 1996; 183: 1271–1275.
- 8 Muzio M, Chinnaiyan AM, Kischkel FC, O’Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM: FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell 1996; 85: 817–827.
- 9 Wang J, Chun HJ, Wong W, Spencer DM, Lenardo MJ: Caspase-10 is an initiator caspase in death receptor signaling. Proc Natl Acad Sci U S A 2001; 98: 13884–13888.
- 10 Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME: Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 1995; 14: 5579–5588.
- 11 Li H, Zhu H, Xu C-j, Yuan J: Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94: 491–501.
- 12 Cory S, Adams JM: The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2002; 2: 647–656.
- 13 Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X: Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91: 479–489.
- 14 Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S: Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci U S A 2002; 99: 1259–1263.
- 15 Saelens X, Festjens N, Walle LV, Gurp Mv, Loo Gv, Vandenabeele P: Toxic proteins released from mitochondria in cell death. Oncogene 2004; 23: 2861–2874.
- 16 Du C, Fang M, Li Y, Li L, Wang X: Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102: 33–42.
- 17 Tewari M, Quan LT, O’Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS, Dixit VM: Yama/CPP32[beta], a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 1995; 81: 801–809.
- 18 Koh DW, Dawson TM, Dawson VL: Mediation of cell death by poly(ADP-ribose) polymerase-1. Pharmacol Res 2005; 52: 5–14.
- 19 Smith S, Baker PN, Symonds EM: Placental apoptosis in normal human pregnancy. Am J Obstet Gynecol 1997; 177: 57–61.
- 20 Levy R, Smith SD, Chandler K, Sadovsky Y, Nelson DM: Apoptosis in human cultured trophoblasts is enhanced by hypoxia and diminished by epidermal growth factor. Am J Physiol Cell Physiol 2000; 278: C982–C988.
- 21 Gavrieli Y, Sherman Y, Ben-Sasson SA: Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 1992; 119: 493–501.
- 22 Leers MP, Kolgen W, Bjorklund V, Bergman T, Tribbick G, Persson B, Bjorklund P, Ramaekers FC, Bjorklund B, Nap M, Jornvall H, Schutte B: Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis. J Pathol 1999; 187: 567–572.
10.1002/(SICI)1096-9896(199904)187:5<567::AID-PATH288>3.0.CO;2-J CASPubMedWeb of Science®Google Scholar
- 23 Pijnenborg R, Bland JM, Robertson WB, Dixon G, Brosens I: The pattern of interstitial trophoblastic invasion of the myometrium in early human pregnancy. Placenta 1981; 2: 303–316.
- 24 Craven CM, Morgan T, Baker PN, Cartwright JE: Decidual spiral artery remodelling begins before cellular interaction with cytotrophoblasts. Placenta 1998; 19: 241–252.
- 25 Ashton SV, Whitley GSJ, Dash PR, Wareing M, Crocker IP, Baker PN, Cartwright JE: Uterine spiral artery remodeling involves endothelial apoptosis induced by extravillous trophoblasts through Fas/FasL interactions. Arterioscler Thromb Vasc Biol 2005; 25: 102–108.
- 26 Dunk C, Petkovic L, Baczyk D, Rossant J, Winterhager E, Lye S: A novel in vitro model of trophoblast-mediated decidual blood vessel remodeling. Lab Invest 2003; 83: 1821–1828.
- 27 Smith SD, Dunk CE, Aplin JD, Harris LK, Jones RL: Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am J Pathol 2009; 174: 1959–1971, Epub 2009 April 6.
- 28 Meekins JW, Luckas MJ, Pijnenborg R, McFadyen IR: Histological study of decidual spiral arteries and the presence of maternal erythrocytes in the intervillous space during the first trimester of normal human pregnancy. Placenta 1997; 18: 459–464.
- 29 Jauniaux E, Hempstock J, Greenwold N, Burton GJ: Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies. Am J Pathol 2003; 162: 115–125.
- 30 Kadyrov M, Kingdom JCP, Huppertz B: Divergent trophoblast invasion and apoptosis in placental bed spiral arteries from pregnancies complicated by maternal anemia and early-onset preeclampsia/intrauterine growth restriction. Am J Obstet Gynecol 2006; 194: 557–563.
- 31 DiFederico E, Genbacev O, Fisher SJ: Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall. Am J Pathol 1999; 155: 293–301.
- 32 Meekins JW, Pijnenborg R: A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. BJOG 1994; 101: 669–674.
- 33 Burton GJ, Jauniaux E, Charnock-Jones DS: The influence of the intrauterine environment on human placental development. Int J Dev Biol 2009; 54: 303–312.
- 34 Hutchinson ES, Brownbill P, Jones NW, Abrahams VM, Baker PN, Sibley CP, Crocker IP: Utero-placental haemodynamics in the pathogenesis of pre-eclampsia. Placenta 2009; 30: 634–641.
- 35 Aardema MW, Oosterhof H, Timmer A, Van Rooy I, Aarnoudse JG: Uterine artery doppler flow and uteroplacental vascular pathology in normal pregnancies and pregnancies complicated by pre-eclampsia and small for gestational age fetuses. Placenta 2001; 22: 405–411.
- 36 Janatpour MJ, Utset MF, Cross JC, Rossant J, Dong J, Israel MA, Fisher SJ: A repertoire of differentially expressed transcription factors that offers insight into mechanisms of human cytotrophoblast differentiation. Dev Genet 1999; 25: 146–157.
- 37 Huppertz B, Bartz C, Kokozidou M: Trophoblast fusion: fusogenic proteins, syncytins and ADAMs, and other prerequisites for syncytial fusion. Micron 2006; 37: 509–517.
- 38 Black S, Kadyrov M, Kaufmann P, Ugele B, Emans N, Huppertz B: Syncytial fusion of human trophoblast depends on caspase 8. Cell Death Differ 2003; 11: 90–98.
- 39 Smith SC, Baker PN: Placental apoptosis is increased in post-term pregnancies. Br J Obstet Gynaecol 1999; 106: 861–862.
- 40 Athapathu H, Jayawardana MA, Senanayaka L: A study of the incidence of apoptosis in the human placental cells in the last weeks of pregnancy. J Obstet Gynaecol 2003; 23: 515–517.
- 41 Hempstock J, Jauniaux E, Greenwold N, Burton GJ: The contribution of placental oxidative stress to early pregnancy failure. Hum Pathol 2003; 34: 1265–1275.
- 42 Cobellis L, De Falco M, Torella M, Trabucco E, Caprio F, Federico E, Manente L, Coppola G, Laforgia V, Cassandro R, Colacurci N, De Luca A: Modulation of Bax expression in physiological and pathological human placentas throughout pregnancy. In Vivo 2007; 21: 777–783.
- 43 Allaire AD, Ballenger KA, Wells SR, Mcmahon MJ, Lessey BA: Placental apoptosis in preeclampsia. Obstet Gynecol 2000; 96: 271–276.
- 44 Leung DN, Smith SC, To KF, Sahota DS, Baker PN: Increased placental apoptosis in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 2001; 184: 1249–1250.
- 45 Ishihara N, Matsuo H, Murakoshi H, Laoag-Fernandez JB, Samoto T, Maruo T: Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation. Am J Obstet Gynecol 2002; 186: 158–166.
- 46 Heazell AE, Buttle HR, Baker PN, Crocker IP: Altered expression of regulators of caspase activity within trophoblast of normal pregnancies and pregnancies complicated by preeclampsia. Reprod Sci 2008; 15: 1034–1043.
- 47 Levy R, Smith SD, Yusuf K, Huettner PC, Kraus FT, Sadovsky Y, Nelson DM: Trophoblast apoptosis from pregnancies complicated by fetal growth restriction is associated with enhanced p53 expression. Am J Obstet Gynecol 2002; 186: 1056–1061.
- 48 Endo H, Okamoto A, Yamada K, Nikaido T, Tanaka T: Frequent apoptosis in placental villi from pregnancies complicated with intrauterine growth restriction and without maternal symptoms. Int J Mol Med 2005; 16: 79–84.
- 49 Smith SC, Baker PN, Symonds EM: Increased placental apoptosis in intrauterine growth restriction. Am J Obstet Gynecol 1997; 177: 1395–1401.
- 50 Wong SY, Ngan HY, Chan CC, Cheung AN: Apoptosis in gestational trophoblastic disease is correlated with clinical outcome and Bcl-2 expression but not Bax expression. Mod Pathol 1999; 12: 1025–1033.
- 51 Chiu PM, Ngan YS, Khoo US, Cheung AN: Apoptotic activity in gestational trophoblastic disease correlates with clinical outcome: assessment by the caspase-related M30 CytoDeath antibody. Histopathology 2001; 38: 243–249.
- 52 Sgarbosa F, Barbisan LF, Brasil MA, Costa E, Calderon IM, Goncalves CR, Bevilacqua E, Rudge MV: Changes in apoptosis and Bcl-2 expression in human hyperglycemic, term placental trophoblast. Diabetes Res Clin Pract 2006; 73: 143–149, Epub 2006 March 24.
- 53 Hamad RR, Bremme K, Kallner A, Sten-Linder M: Increased levels of an apoptotic product in the sera from women with pre-eclampsia. Scand J Clin Lab Invest 2009; 69: 204–208.
- 54 Burton GJ, Skepper JN, Hempstock J, Cindrova T, Jones CJP, Jauniaux E: A reappraisal of the contrasting morphological appearances of villous cytotrophoblast cells during early human pregnancy; evidence for both apoptosis and primary necrosis. Placenta 2003; 24: 297–305.
- 55 Smith SC, Leung TN, To KF, Baker PN: Apoptosis is a rare event in first-trimester placental tissue. Am J Obstet Gynecol 2000; 183: 697–699.
- 56 De Falco M, Fedele V, Cobellis L, Mastrogiacomo A, Leone S, Giraldi D, De Luca B, Laforgia V, De Luca A: Immunohistochemical distribution of proteins belonging to the receptor-mediated and the mitochondrial apoptotic pathways in human placenta during gestation. Cell Tissue Res 2004; 318: 599–608, Epub 2004 October 2.
- 57 Huppertz B, Frank HG, Reister F, Kingdom J, Korr H, Kaufmann P: Apoptosis cascade progresses during turnover of human trophoblast: analysis of villous cytotrophoblast and syncytial fragments in vitro. Lab Invest 1999; 79: 1687–1702.
- 58 Kadyrov M, Kaufmann P, Huppertz B: Expression of a cytokeratin 18 neo-epitope is a specific marker for trophoblast apoptosis in human placenta. Placenta 2001; 22: 44–48.
- 59 Huppertz B, Kadyrov M, Kingdom JCP: Apoptosis and its role in the trophoblast. Am J Obstet Gynecol 2006; 195: 29–39.
- 60 Knight M, Redman CW, Linton EA, Sargent IL: Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. Br J Obstet Gynaecol 1998; 105: 632–640.
- 61 Redman CWG, Sargent IL: Placental debris, oxidative stress and pre-eclampsia. Placenta 2000; 21: 597–602.
- 62 Burton GJ, Jones CJ: Syncytial knots, sprouts, apoptosis, and trophoblast deportation from the human placenta. Taiwan J Obstet Gynecol 2009; 48: 28–37.
- 63 Ratts VS, Tao X-J, Webster CB, Swanson PE, Smith SD, Brownbill P, Krajewski S, Reed JC, Tilly JL, Nelson DM: Expression of BCL-2, BAX and BAK in the trophoblast layer of the term human placenta: a unique model of apoptosis within a syncytium. Placenta 2000; 21: 361–366.
- 64 Crocker IP, Tansinda DM, Jones CJ, Baker PN: The influence of oxygen and tumor necrosis factor-alpha on the cellular kinetics of term placental villous explants in culture. J Histochem Cytochem 2004; 52: 749–757.
- 65 Crocker IP, Cooper S, Ong SC, Baker PN: Differences in apoptotic susceptibility of cytotrophoblasts and syncytiotrophoblasts in normal pregnancy to those complicated with preeclampsia and intrauterine growth restriction. Am J Pathol 2003; 162: 637–643.
- 66 Crocker IP, Tansinda DM, Baker PN: Altered cell kinetics in cultured placental villous explants in pregnancies complicated by pre-eclampsia and intrauterine growth restriction. J Pathol 2004; 204: 11–18.
- 67 Moll SJ, Jones CJ, Crocker IP, Baker PN, Heazell AE: Epidermal growth factor rescues trophoblast apoptosis induced by reactive oxygen species. Apoptosis 2007; 12: 1611–1622.
- 68 Heazell AEP, Crocker IP: Live and let die – regulation of villous trophoblast apoptosis in normal and abnormal pregnancies. Placenta 2008; 29: 772–783.
- 69 Abrahams VM, Straszewski-Chavez SL, Guller S, Mor G: First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis. Mol Hum Reprod 2004; 10: 55–63.
- 70 Bai X, Williams JL, Greenwood SL, Baker PN, Aplin JD, Crocker IP: A placental protective role for trophoblast-derived TNF-related apoptosis-inducing ligand (TRAIL). Placenta 2009; 30: 855–860, Epub 2009 August 11.
- 71 Quenby S, Brazeau C, Drakeley A, Lewis-Jones D, Vince G: Oncogene and tumour suppressor gene products during trophoblast differentiation in the first trimester. Mol Hum Reprod 1998; 4: 477–481.
- 72 Haidacher S, Blaschitz A, Desoye G, Dohr G: Cell proliferation and apoptosis: Immunohistochemical evidence of p53 protein in human placenta and choriocarcinoma cell lines. Hum Reprod 1995; 10: 983–988.
- 73 Shi YF, Xie X, Zhao CL, Ye DF, Lu SM, Hor JJ, Pao CC: Lack of mutation in tumour-suppressor gene p53 in gestational trophoblastic tumours. Br J Cancer 1996; 73: 1216–1219.
- 74 Cheung AN, Shen DH, Khoo US, Chiu MP, Tin VP, Chung LP, Ngan HY: Immunohistochemical and mutational analysis of p53 tumor suppressor gene in gestational trophoblastic disease: correlation with mdm2, proliferation index, and clinicopathologic parameters. Int J Gynecol Cancer 1999; 9: 123–130.
- 75 Fulop V, Mok SC, Genest DR, Gati I, Doszpod J, Berkowitz RS: p53, p21, Rb and mdm2 oncoproteins. Expression in normal placenta, partial and complete mole, and choriocarcinoma. J Reprod Med 1998; 43: 119–127.
- 76 Heazell AEP, Lacey HA, Jones CJP, Huppertz B, Baker PN, Crocker IP: Effects of oxygen on cell turnover and expression of regulators of apoptosis in human placental trophoblast. Placenta 2008; 29: 175–186.
- 77 De Falco M, Cobellis L, Giraldi D, Mastrogiacomo A, Perna A, Colacurci N, Miele L, De Luca A: Expression and distribution of notch protein members in human placenta throughout pregnancy. Placenta 2007; 3: 118–126.
- 78 Mayhew TM, Wijesekara J, Baker PN, Ong SS: Morphometric evidence that villous development and fetoplacental angiogenesis are compromised by intrauterine growth restriction but not by pre-eclampsia. Placenta 2004; 25: 829–833.
- 79 Daayana S, Baker P, Crocker I: An image analysis technique for the investigation of variations in placental morphology in pregnancies complicated by preeclampsia with and without intrauterine growth restriction. J Soc Gynecol Investig 2004; 11: 545–552.
- 80 Heazell AEP, Brown LM, Baker P, Crocker I: Expression of oncoproteins p53 and Mdm2 within trophoblast of normal and pre-eclamptic pregnancies. J Soc Gynecol Investig 2005; 12: 362A.
- 81 Soleymanlou N, Jurisicova A, Wu Y, Chijiiwa M, Ray JE, Detmar J, Todros T, Zamudio S, Post M, Caniggia I: Hypoxic switch in mitochondrial myeloid cell leukemia factor-1/Mtd apoptotic rheostat contributes to human trophoblast cell death in preeclampsia. Am J Pathol 2007; 171: 496–506.
- 82 Jeschke U, Schiessl B, Mylonas I, Kunze S, Kuhn C, Schulze S, Friese K, Mayr D: Expression of the proliferation marker Ki-67 and of p53 tumor protein in trophoblastic tissue of preeclamptic, HELLP, and intrauterine growth-restricted pregnancies. Int J Gynecol Pathol 2006; 25: 354–360.
- 83 Davy P, Nagata M, Bullard P, Fogelson NS, Allsopp R: Fetal growth restriction is associated with accelerated telomere shortening and increased expression of cell senescence markers in the placenta. Placenta 2009; 30: 539–542, Epub 2009 April 8.
- 84 Fox H: The significance of villous syncytial knots in the human placenta. J Obstet Gynaecol Br Commonw 1965; 72: 347–355.
- 85 Heazell AEP, Moll SJ, Jones CJP, Baker PN, Crocker IP: Formation of syncytial knots is increased by hyperoxia, hypoxia and reactive oxygen species. Placenta 2007; 28(Suppl. 1): S33–S40.
- 86 Goswami D, Tannetta DS, Magee LA, Fuchisawa A, Redman CW, Sargent IL, Von Dadelszen P: Excess syncytiotrophoblast microparticle shedding is a feature of early-onset pre-eclampsia, but not normotensive intrauterine growth restriction. Placenta 2006; 27: 56–61, Epub 2005 January 25.
- 87 Orozco AF, Jorgez CJ, Ramos-Perez WD, Popek EJ, Yu X, Kozinetz CA, Bischoff FZ, Lewis DE: Placental release of distinct DNA-associated micro-particles into maternal circulation: reflective of gestation time and preeclampsia. Placenta 2009; 30: 891–897, Epub 2009 August 18.
- 88 Zhong XY, Holzgreve W, Hahn S: The levels of circulatory cell free fetal DNA in maternal plasma are elevated prior to the onset of preeclampsia. Hypertens Pregnancy 2002; 21: 77–83.
- 89 Orozco AF, Bischoff FZ, Horne C, Popek E, Simpson JL, Lewis DE: Hypoxia-induced membrane-bound apoptotic DNA particles: potential mechanism of fetal DNA in maternal plasma. Ann N Y Acad Sci 2006; 1075: 57–62.
- 90 Tjoa ML, Cindrova-Davies T, Spasic-Boskovic O, Bianchi DW, Burton GJ: Trophoblastic oxidative stress and the release of cell-free feto-placental DNA. Am J Pathol 2006; 169: 400–404.
- 91 Sifakis S, Zaravinos A, Maiz N, Spandidos DA, Nicolaides KH: First-trimester maternal plasma cell-free fetal DNA and preeclampsia. Am J Obstet Gynecol 2009; 201: 472, Epub 2009 July 24.
- 92 Luo SS, Ishibashi O, Ishikawa G, Ishikawa T, Katayama A, Mishima T, Takizawa T, Shigihara T, Goto T, Izumi A, Ohkuchi A, Matsubara S, Takeshita T: Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes. Biol Reprod 2009; 81: 717–729, Epub 2009 June 3.
- 93 Von Dadelszen P, Hurst G, Redman CW: Supernatants from co-cultured endothelial cells and syncytiotrophoblast microvillous membranes activate peripheral blood leukocytes in vitro. Hum Reprod 1999; 14: 919–924.
- 94 Gupta A, Hasler P, Gebhardt S, Holzgreve W, Hahn S: Occurrence of neutrophil extracellular DNA traps (NETs) in pre-eclampsia: a link with elevated levels of cell-free DNA? Ann N Y Acad Sci 2006; 1075: 118–122.
- 95 Aly AS, Khandelwal M, Zhao J, Mehmet AH, Sammel MD, Parry S: Neutrophils are stimulated by syncytiotrophoblast microvillous membranes to generate superoxide radicals in women with preeclampsia. Am J Obstet Gynecol 2004; 190: 252–258.
- 96 Germain SJ, Sacks GP, Sooranna SR, Sargent IL, Redman CW: Systemic inflammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles. J Immunol 2007; 178: 5949–5956.
- 97 Messerli M, May K, Hansson SR, Schneider H, Holzgreve W, Hahn S, Rusterholz C: Feto-maternal interactions in pregnancies: placental microparticles activate peripheral blood monocytes. Placenta 2010; 31: 106–112.
- 98 Luppi P, DeLoia JA: Monocytes of preeclamptic women spontaneously synthesize pro-inflammatory cytokines. Clin Immunol 2006; 118: 268–275.
- 99 Cockell AP, Learmont JG, Smarason AK, Redman CW, Sargent IL, Poston L: Human placental syncytiotrophoblast microvillous membranes impair maternal vascular endothelial function. Br J Obstet Gynaecol 1997; 104: 235–240.
- 100 Hoegh AM, Tannetta D, Sargent I, Borup R, Nielsen FC, Redman C, Sorensen S, Hviid TV: Effect of syncytiotrophoblast microvillous membrane treatment on gene expression in human umbilical vein endothelial cells. BJOG 2006; 113: 1270–1279.