[en] Trophoblast invasion is a key process during human placentation. This event constitutes the basis of the conversion of the uterine spiral arteries, a process which allows an adequate vascular connection between the intervillous space and the maternal blood flow. Trophoblast invasion is transient, with stringent spatial and temporal control. Preeclampsia, a leading cause of maternal and fetal mortality and morbidity, is associated with decreased, shallow trophoblastic invasion. In this article, we review the molecular mechanisms of trophoblast invasion, and its mechanisms of regulation. Insights into the etiopathogenesis of preeclampsia will also be detailed.
Berndt, Sarah ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Simon, N.
Coulon, C.
Le Goarant, J.
Munaut, Carine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Frankenne, Francis
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
Language :
English
Title :
Trophoblast Invasion and Placentation: Molecular Mechanisms and Regulation
Hertig AT, Rock J, Adams EC, Menkin MC: Thirty-four fertilized human ova, good, bad and indifferent, recovered from 210 women of known fertility; a study of biologic wastage in early human pregnancy. Pediatrics 1959;23:202-211.
Brosens I, Dixon HG: The anatomy of the maternal side of the placenta. J Obstet Gynaecol Br Commonw 1966;73:357-363.
Enders AC: Fine structure of anchoring villi of the human placenta. Am J Anat 1968;122:419-451.
Enders AC: Cytology of human early implantation. Res Reprod 1976;8:1-2.
Fisher SJ, Cui TY, Zhang L, Hartman L, Grahl K, Zhang GY, Tarpey J, Damsky CH: Adhesive and degradative properties of human placental cytotrophoblast cells in vitro. J Cell Biol 1989;109:891-902.
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.
Kurman RJ, Main CS, Chen HC: Intermediate trophoblast: A distinctive form of trophoblast with specific morphological, biochemical and functional features. Placenta 1984;5:349-369.
Yeh IT, Kurman RJ: Functional and morphologic expressions of trophoblast. Lab Invest 1989;61:1-4.
Pijnenborg R, Robertson WB, Brosens I, Dixon G: Review article: Trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals. Placenta 1981;2:71-91.
Pijnenborg R, Bland JM, Robertson WB, Brosens I: Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta 1983;4:397-413.
Liotta LA, Rao CN, Wewer UM: Biochemical interactions of tumor cells with the basement membrane. Annu Rev Biochem 1986;55:1037-1057.
Norwitz ER, Schust DJ, Fisher SJ: Implantation and the survival of early pregnancy. N Engl J Med 2001;345:1400-1408.
Shih IM, Kurman RJ: New concepts in trophoblastic growth and differentiation with practical application for the diagnosis of gestational trophoblastic disease. Verh Dtsch Ges Pathol 1997;81:266-272.
Damsky CH, Fitzgerald ML, Fisher SJ: Distribution patterns of extracellular matrix components and adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the invasive pathway, in vivo. J Clin Invest 1992;89:210-222.
Damsky CH, Librach C, Lim KH, Fitzgerald ML, McMaster MT, Janatpour M, Zhou Y, Logan SK, Fisher SJ: Integrin switching regulates normal trophoblast invasion. Development 1994;120:3657-3666.
Zhou Y, Damsky CH, Chiu K, Roberts JM, Fisher SJ: Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts. J Clin Invest 1993;91:950-960.
Zhou Y, Fisher SJ, Janatpour M, Genbacev O, Dejana E, Wheelock M, Damsky CH: Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J Clin Invest 1997;99:2139-2151.
Zhou Y, Genbacev O, Damsky CH, Fisher SJ: Oxygen regulates human cytotrophoblast differentiation and invasion: Implications for endovascular invasion in normal pregnancy and in preeclampsia. J Reprod Immunol 1998;39:197-213.
Damsky CH, Fisher SJ: Trophoblast pseudo-vasculogenesis: Faking it with endothelial adhesion receptors. Curr Opin Cell Biol 1998;10:660-666.
Murray MJ, Lessey BA: Embryo implantation and tumor metastasis: Common pathways of invasion and angiogenesis. Semin Reprod Endocrinol 1999;17:275-290.
Hemberger M, Nozaki T, Masutani M, Cross JC: Differential expression of angiogenic and vasodilatory factors by invasive trophoblast giant cells depending on depth of invasion. Dev Dyn 2003;227:185-191.
Ilic D, Genbacev O, Jin F, Caceres E, Almeida EA, Bellingard-Dubouchaud V, Schaefer EM, Damsky CH, Fisher SJ: Plasma membrane-associated pY397FAK is a marker of cytotrophoblast invasion in vivo and in vitro. Am J Pathol 2001;159:93-108.
Bamberger AM, Sudahl S, Loning T, Wagener C, Bamberger CM, Drakakis P, Coutifaris C, Makrigiannakis A: The adhesion molecule CEACAM1 (CD66a, C-CAM, BGP) is specifically expressed by the extravillous intermediate trophoblast. Am J Pathol 2000;156:1165-1170.
Bamberger AM, Sudahl S, Wagener C, Loning T: Expression pattern of the adhesion molecule CEACAM1 (C-CAM, CD66a, BGP) in gestational trophoblastic lesions. Int J Gynecol Pathol 2001;20:160-165.
Genbacev OD, Prakobphol A, Foulk RA, Krtolica AR, Ilic D, Singer MS, Yang ZQ, Kiessling LL, Rosen SD, Fisher SJ: Trophoblast L-selectin-mediated adhesion at the maternal-fetal interface. Science 2003;299:405-408.
Higuchi T, Fujiwara H, Egawa H, Sato Y, Yoshioka S, Tatsumi K, Itoh K, Maeda M, Fujita J, Fujii S: Cyclic AMP enhances the expression of an extravillous trophoblast marker, melanoma cell adhesion molecule, in choriocarcinoma cell JEG3 and human chorionic villous explant cultures. Mol Hum Reprod 2003;9:359-366.
van den Brûle F, Califice S, Castronovo V: Expression of galectins in cancer: A critical review. Glycoconj J 2004;19:537-542.
van den Brûle FA, Price J, Sobel ME, Lambotte R, Castronovo V: Inverse expression of two laminin binding proteins, 67LR and galectin-3, correlates with the invasive phenotype of trophoblastic tissue. Biochem Biophys Res Commun 1994;201:388-393.
Maquoi E, van den Brûle FA, Castronovo V, Foidart JM: Changes in the distribution pattern of galectin-1 and galectin-3 in human placenta correlates with the differentiation pathways of trophoblasts. Placenta 1997;18:433-439.
Zhou Y, Damsky CH, Fisher SJ: Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest 1997;99:2152-2164.
Lim KH, Zhou Y, Janatpour M, McMaster M, Bass K, Chun SH, Fisher SJ: Human cytotrophoblast differentiation/invasion is abnormal in pre-eclampsia. Am J Pathol 1997;151:1809-1818.
Fisher SJ, Leitch MS, Kantor MS, Basbaum CB, Kramer RH: Degradation of extracellular matrix by the trophoblastic cells of first-trimester human placentas. J Cell Biochem 1985;27:31-41.
Bischof P, Martelli M: Current topic: Proteolysis in the penetration phase of the implantation process. Placenta 1992;13:17-24.
Bischof P, Martelli M, Campana A, Itoh Y, Ogata Y, Nagase H: Importance of matrix metalloproteinases in human trophoblast invasion. Early Pregnancy 1995;1:263-269.
Puistola U, Ronnberg L, Martikainen H, Tuipeenniemi-Hujanen T: The human embryo produces basement membrane collagen (type IV collagen)-degrading protease activity. Hum Reprod 1989;4:309-311.
Huppertz B, Kertschanska S, Demir AY, Frank HG, Kaufmann P: Immunohistochemistry of matrix metalloproteinases (MMP), their substrates, and their inhibitors (TIMP) during trophoblast invasion in the human placenta. Cell Tissue Res 1998;291:133-148.
Yagel S, Parhar RS, Jeffrey JJ, Lala PK: Normal nonmetastatic human trophoblast cells share invitro invasive properties of malignant cells. J Cell Physiol 1988;136:455-462.
Kliman HJ, Feinberg RF: Human trophoblast-extracellular matrix (ECM) interactions in vitro: ECM thickness modulates morphology and proteolytic activity. Proc Natl Acad Sci USA 1990;87:3057-3061.
Graham CH, Connelly I, MacDougall JR, Kerbel RS, Stetler-Stevenson WG, Lala PK: Resistance of malignant trophoblast cells to both the anti-proliferative and anti-invasive effects of transforming growth factor-beta. Exp Cell Res 1994;214:93-99.
Shimonovitz S, Hurwitz A, Dushnik M, Anteby E, Geva-Eldar T, Yagel S: Developmental regulation of the expression of 72 and 92 kd type IV collagenases in human trophoblasts: A possible mechanism for control of trophoblast invasion. Am J Obstet Gynecol 1994;171:832-838.
Librach CL, Werb Z, Fitzgerald ML, Chiu K, Corwin NM, Esteves RA, Grobelny D, Galardy R, Damsky CH, Fisher SJ: 92-kD type IV collagenase mediates invasion of human cytotrophoblasts. J Cell Biol 1991;113:437-449.
Cross JC, Werb Z, Fisher SJ: Implantation and the placenta: Key pieces of the development puzzle. Science 1994;266:1508-1518.
Tarrade A, Goffin F, Munaut C, Lai-Kuen R, Tricottet V, Foidart JM, Vidaud M, Frankenne F, Evain-Brion D: Effect of matrigel on human extravillous trophoblasts differentiation: Modulation of protease pattern gene expression. Biol Reprod 2002;67:1628-1637.
Bass KE, Li H, Hawkes SP, Howard E, Bullen E, Vu TK, McMaster M, Janatpour M, Fisher SJ: Tissue inhibitor of metalloproteinase-3 expression is upregulated during human cytotrophoblast invasion in vitro. Dev Genet 1997;21:61-67.
Schatz F, Krikun G, Runic R, Wang EY, Hausknecht V, Lockwood CJ: Implications of decidualization-associated protease expression in implantation and menstruation. Semin Reprod Endocrinol 1999;17:3-12.
Maquoi E, Polette M, Nawrocki B, Bischof P, Noel A, Pintiaux A, Santavicca M, Schaaps JP, Pijnenborg R, Birembaut P, Foidart JM: Expression of stromelysin-3 in the human placenta and placental bed. Placenta 1997;18:277-285.
Zini JM, Murray SC, Graham CH, Lala PK, Kariko K, Barnathan ES, Mazar A, Henkin J, Cines DB, McCrae KR: Characterization of urokinase receptor expression by human placental trophoblasts. Blood 1992;79:2917-2929.
Graham CH, McCrae KR: Altered expression of gelatinase and surface-associated plasminogen activator activity by trophoblast cells isolated from placentas of preeclamptic patients. Am J Obstet Gynecol 1996;175:555-562.
O'Brien PJ, Koi H, Parry S, Brass LF, Strauss JF 3rd, Wang LP, Tomaszewski JE, Christenson LK: Thrombin receptors and protease-activated receptor-2 in human placentation: Receptor activation mediates extravillous trophoblast invasion in vitro. Am J Pathol 2003;163:1245-1254.
Afonso S, Romagnano L, Babiarz B: The expression and function of cystatin C and cathepsin B and cathepsin L during mouse embryo implantation and placentation. Development 1997;124:3415-3425.
Vicovac L, Jones CJ, Aplin JD: Trophoblast differentiation during formation of anchoring villi in a model of the early human placenta in vitro. Placenta 1995;16:41-56.
Goffin F, Munaut C, Malassine A, Evain-Brion D, Frankenne F, Fridman V, Dubois M, Uzan S, Merviel P, Foidart JM: Evidence of a limited contribution of feto-maternal interactions to trophoblast differentiation along the invasive pathway. Tissue Antigens 2003;62:104-116.
Shimonovitz S, Hurwitz A, Hochner-Celnikier D, Dushnik M, Anteby E, Yagel S: Expression of gelatinase B by trophoblast cells: Down-regulation by progesterone. Am J Obstet Gynecol 1998;178:457-461.
Emonard H, Christiane Y, Smet M, Grimaud JA, Foidart JM: Type IV and interstitial collagenolytic activities in normal and malignant trophoblast cells are specifically regulated by the extracellular matrix. Invasion Metastasis 1990;10:170-177.
Drake PM, Red-Horse K, Fisher SJ: Reciprocal chemokine receptor and ligand expression in the human placenta: Implications for cytotrophoblast differentiation. Dev Dyn 2004;229:877-885.
Graham CH, Lysiak JJ, McCrae KR, Lala PK: Localization of transforming growth factor-beta at the human fetal-maternal interface: Role in trophoblast growth and differentiation. Biol Reprod 1992;46:561-572.
Hofmann GE, Horowitz GM, Scott RT Jr, Navot D: Transforming growth factor-alpha in human implantation trophoblast: Immunohistochemical evidence for autocrine/paracrine function. J Clin Endocrinol Metab 1993;76:781-785.
Lysiak JJ, Hunt J, Pringle GA, Lala PK: Localization of transforming growth factor beta and its natural inhibitor decorin in the human placenta and decidua throughout gestation. Placenta 1995;16:221-231.
Feinberg RF, Kliman HJ, Wang CL: Transforming growth factor-beta stimulates trophoblast oncofetal fibronectin synthesis in vitro: Implications for trophoblast implantation in vivo. J Clin Endocrinol Metab 1994;78:1241-1248.
Xu G, Guimond MJ, Chakraborty C, Lala PK: Control of proliferation, migration, and invasiveness of human extravillous trophoblast by decorin, a decidual product. Biol Reprod 2002;67:681-689.
Jokhi PP, King A, Loke YW: Reciprocal expression of epidermal growth factor receptor (EGF-R) and c-erbB2 by non-invasive and invasive human trophoblast populations. Cytokine 1994;6:433-442.
Bischof P, Campana A: Trophoblast differentiation and invasion: Its significance for human embryo implantation. Early Pregnancy 1997;3:81-95.
Hofmann GE, Scott RT Jr., Bergh PA, Deligdisch L: Immunohistochemical localization of epidermal growth factor in human endometrium, decidua, and placenta. J Clin Endocrinol Metab 1991;73:882-887.
Lala PK, Hamilton GS: Growth factors, proteases and protease inhibitors in the maternal-fetal dialogue. Placenta 1996;17:545-555.
Lysiak JJ, Johnson GR, Lala PK: Localization of amphiregulin in the human placenta and decidua throughout gestation: Role in trophoblast growth. Placenta 1995;16:359-366.
Li RH, Zhuang LZ: The effects of growth factors on human normal placental cytotrophoblast cell proliferation. Hum Reprod 1997;12:830-834.
Cullinan EB, Abbondanzo SJ, Anderson PS, Pollard JW, Lessey BA, Stewart CL: Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Proc Natl Acad Sci USA 1996;93:3115-3120.
Nachtigall MJ, Kliman HJ, Feinberg RF, Olive DL, Engin O, Arici A: The effect of leukemia inhibitory factor (LIF) on trophoblast differentiation: A potential role in human implantation. J Clin Endocrinol Metab 1996;81:801-806.
Caniggia I, Grisaru-Gravnosky S, Kuliszewsky M, Post M, Lye SJ: Inhibition of TGF-beta 3 restores the invasive capability of extravillous trophoblasts in preeclamptic pregnancies. J Clin Invest 1999;103:1641-1650.
Caniggia I, Mostachfi H, Winter J, Gassmann M, Lye SJ, Kuliszewski M, Post M: Hypoxiainducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3). J Clin Invest 2000;105:577-587.
Das C, Kumar VS, Gupta S, Kumar S: Network of cytokines, integrins and hormones in human trophoblast cells. J Reprod Immunol 2002;53:257-268.
Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, Alitalo K, Damsky C, Fisher SJ: Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol 2002;160:1405-1423.
Gonzalez RR, Devoto L, Campana A, Bischof P: Effects of leptin, interleukin-1alpha, interleukin-6, and transforming growth factor-beta on markers of trophoblast invasive phenotype: Integrins and metalloproteinases. Endocrine 2001;15:157-164.
Jones JI, Gockerman A, Busby WH Jr, Wright G, Clemmons DR: Insulin-like growth factor binding protein 1 stimulates cell migration and binds to the alpha 5 beta 1 integrin by means of its ArgGly-Asp sequence. Proc Natl Acad Sci USA 1993;90:10553-10557.
Han VK, Bassett N, Walton J, Challis JR: The expression of insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) genes in the human placenta and membranes: Evidence for IGF-IGFBP interactions at the feto-maternal interface. J Clin Endocrinol Metab 1996;81:2680-2693.
Zygmunt M, Hahn D, Munstedt K, Bischof P, Lang U: Invasion of cytotrophoblastic JEG-3 cells is stimulated by hCG in vitro. Placenta 1998;19:587-593.
Bass KE, Morrish D, Roth I, Bhardwaj D, Taylor R, Zhou Y, Fisher SJ: Human cytotrophoblast invasion is up-regulated by epidermal growth factor: Evidence that paracrine factors modify this process. Dev Biol 1994;164:550-561.
Nasu K, Zhou Y, McMaster MT, Fisher SJ: Upregulation of human cytotrophoblast invasion by hepatocyte growth factor. J Reprod Fertil Suppl 2000;55:73-80.
Sawicki G, Radomski MW, Winkler-Lowen B, Krzymien A, Guilbert LJ: Polarized release of matrix metalloproteinase-2 and -9 from cultured human placental syncytiotrophoblasts. Biol Reprod 2000;63:1390-1395.
Librach CL, Feigenbaum SL, Bass KE, Cui TY, Verastas N, Sadovsky Y, Quigley JP, French DL, Fisher SJ: Interleukin-1 beta regulates human cytotrophoblast metalloproteinase activity and invasion in vitro. J Biol Chem 1994;269:17125-17131.
Sheth KV, Roca GL, al-Sedairy ST, Parhar RS, Hamilton CJ, al-Abdul Jabbar F: Prediction of successful embryo implantation by measuring interleukin-1-alpha and immunosuppressive factor(s) in preimplantation embryo culture fluid. Fertil Steril 1991;55:952-957.
Pollard JW, Bartocci A, Arceci R, Orlofsky A, Ladner MB, Stanley ER: Apparent role of the macrophage growth factor, CSF-1, in placental development. Nature 1987;330:484-486.
Jokhi PP, Chumbley G, King A, Gardner L, Loke YW: Expression of the colony stimulating factor-1 receptor (c-fms product) by cells at the human uteroplacental interface. Lab Invest 1993;68:308-320.
Hoshina M, Nishio A, Bo M, Boime I, Mochizuki M: The expression of oncogene fms in human chorionic tissue. Nippon Sanka Fujinka Gakkai Zasshi 1985;37:2791-2798.
Sharkey AM, Dellow K, Blayney M, Macnamee M, Charnock-Jones S, Smith SK: Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos. Biol Reprod 1995;53:974-981.
Hamilton GS, Lysiak JJ, Watson AJ, Lala PK: Effects of colony stimulating factor-1 on human extravillous trophoblast growth and invasion. J Endocrinol 1998;159:69-77.
Moffett A, Loke YW: The immunological paradox of pregnancy: A reappraisal. Placenta 2004;25:1-8.
Le Bouteiller P, Solier C, Proll J, Aguerre-Girr M, Fournel S, Lenfant F: Placental HLA-G protein expression in vivo: Where and what for? Hum Reprod Update 1999;5:223-233.
Rouas-Freiss N, Marchal RE, Kirszenbaum M, Dausset J, Carosella ED: The alpha1 domain of HLA-G1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: Is HLA-G the public ligand for natural killer cell inhibitory receptors? Proc Natl Acad Sci USA 1997;94:5249-5254.
Le Bouteiller P, Pizzato N, Barakonyi A, Solier C: HLA-G, pre-eclampsia, immunity and vascular events. J Reprod Immunol 2003;59:219-234.
Navarro F, Llano M, Bellon T, Colonna M, Geraghty DE, Lopez-Botet M: The ILT2(LIR1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells. Eur J Immunol 1999;29:277-283.
Colbern GT, Chiang MH, Main EK: Expression of the nonclassic histocompatibility antigen HLA-G by preeclamptic placenta. Am J Obstet Gynecol 1994;170:1244-1250.
Hara N, Fujii T, Yamashita T, Kozuma S, Okai T, Taketani Y: Altered expression of human leukocyte antigen G (HLA-G) on extravillous trophoblasts in preeclampsia: Immunohistological demonstration with anti-HLA-G specific antibody '87G' and anti-cytokeratin antibody 'CAMS.2'. Am J Reprod Immunol 1996;36:349-358.
Goldman-Wohl DS, Ariel I, Greenfield C, Hochner-Celnikier D, Cross J, Fisher S, Yagel S: Lack of human leukocyte antigen-G expression in extravillous trophoblasts is associated with preeclampsia. Mol Hum Reprod 2000;6:88-95.
Dekker GA, Sibai BM: Etiology and pathogenesis of preeclampsia: Current concepts. Am J Obstet Gynecol 1998;179:1359-1375.
Thellin O, Coumans B, Zorzi W, Igout A, Heinen E: Tolerance to the foeto-placental 'graft': Ten ways to support a child for nine months. Curr Opin Immunol 2000;12:731-737.
Cross JC: Genetic insights into trophoblast differentiation and placental morphogenesis. Semin Cell Dev Biol 2000;11:105-113.
Loregger T, Pollheimer J, Knofler M: Regulatory transcription factors controlling function and differentiation of human trophoblast - a review. Placenta 2003;24(suppl A):S104-S110.
Doneda L, Bulfamante G, Grimoldi MG, Volpi L, Larizza L: Localization of fos, jun, kit and SCF mRNA in human placenta throughout gestation using in situ RT-PCR. Early Pregnancy 1997;3:265-271.
Dakour J, Li H, Chen H, Morrish DW: EGF promotes development of a differentiated trophoblast phenotype having c-myc and junB proto-oncogene activation. Placenta 1999;20:119-126.
Schorpp-Kistner M, Wang ZQ, Angel P, Wagner EF: JunB is essential for mammalian placentation. EMBO J 1999;18:934-948.
Wu KJ, Grandori C, Amacker M, Simon-Vermot N, Polack A, Lingner J, Dalla-Favera R: Direct activation of TERT transcription by c-MYC. Nat Genet 1999;21:220-224.
Pfeifer-Ohlsson S, Goustin AS, Rydnert J, Wahlstrom T, Bjersing L, Stehelin D, Ohlsson R: Spatial and temporal pattern of cellular myc oncogene expression in developing human placenta: Implications for embryonic cell proliferation. Cell 1984;38:585-596.
Goustin AS, Betsholtz C, Pfeifer-Ohlsson S, Persson H, Rydnert J, Bywater M, Holmgren G, Heldin CH, Westermark B, Ohlsson R: Coexpression of the sis and myc proto-oncogenes in developing human placenta suggests autocrine control of trophoblast growth. Cell 1985;41:301-312.
Wenger RH, Gassmann M: Oxygen(es) and the hypoxia-inducible factor-1. Biol Chem 1997;378:609-616.
Wang GL, Semenza GL: General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 1993;90:4304-4308.
Wang GL, Jiang BH, Rue EA, Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995;92:5510-5514.
Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399:271-275.
Genbacev O, Joslin R, Damsky CH, Polliotti BM, Fisher SJ: Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. J Clin Invest 1996;97:540-550.
Genbacev O, Zhou Y, Ludlow JW, Fisher SJ: Regulation of human placental development by oxygen tension. Science 1997;277:1669-1672.
Hustin J, Schaaps JP: Echographic [corrected] and anatomic studies of the maternotrophoblastic border during the first trimester of pregnancy. Am J Obstet Gynecol 1987;157:162-168.
Rodesch F, Simon P, Donner C, Jauniaux E: Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol 1992;80:283-285.
Burton GJ, Jauniaux E, Watson AL: Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: The Boyd collection revisited. Am J Obstet Gynecol 1999;181:718-724.
Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ: Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am J Pathol 2000;157:2111-2122.
Genbacev O, Krtolica A, Kaelin W, Fisher SJ: Human cytotrophoblast expression of the von Hippel-Lindau protein is downregulated during uterine invasion in situ and upregulated by hypoxia in vitro. Dev Biol 2001;233:526-536.
Proll J, Blaschitz A, Hartmann M, Thalhamer J, Dohr G: Human first-trimester placenta intra-arterial trophoblast cells express the neural cell adhesion molecule. Early Pregnancy 1996;2:271-275.