绒毛外滋养细胞在妊娠子宫螺旋动脉重塑过程中的作用机制研究
|
摘要
第一部分子痫前期胎盘滋养细胞中MMP-9及FasL表达的研究
目的
探讨MMP-9和FasL在子痫前期发病机制中的作用及两者间的关联。
方法
采用免疫组织化学法检测48例子痫前期孕妇(重度子痫前24例,轻度子痫前期24例)及24例正常晚期妊娠孕妇胎盘中MMP-9和FasL的表达定位及强度。
结果
MMP-9主要表达于胎盘合体滋养细胞细胞质和细胞膜内,FasL主要表达于胎盘合体滋养细胞细胞质和细胞膜内。轻、重度子痫前期组MMP-9表达水平明显低于正常晚孕组(P<0.05)。轻、重度子痫前期组FasL表达水平明显高于正常晚孕组(P<0.05)。胎盘组织中MMP-9与FasL表达水平呈负相关(r=-0.700,P<0.05)。
结论
1、子痫前期胎盘滋养细胞中MMP-9与FasL表达异常,使胎盘形成时滋养细胞入侵减少及血管重塑障碍,可能与子痫前期的发病机制有关。
2、子痫前期胎盘滋养细胞中MMP-9与FasL的表达水平呈负相关,可能滋养细胞的侵入与其致内皮细胞凋亡作用之间存在关联,共同参与子痫前期的发生。
第二部分绒毛外滋养细胞中MMP-9表达对FasL分泌的作用和机制的研究
目的
通过脂质体转染MMP-9siRNA,探讨绒毛外滋养细胞株TEV-1中基质金属蛋白酶-9(MMP-9)对可溶性Fas配体(sFasL)表达的调控。
方法
1、化学合成MMP-9siRNA,通过脂质体转染绒毛外滋养细胞株TEV-1。2、RealTime RT-PCR、ELISA检测MMP-9siRNA转染效率,ELISA检测细胞内、外FasL蛋白表达的变化。3、给予外源性MMP-9,ELISA检测细胞内、外FasL蛋白表达的变化。
结果
1、转染后,MMP-9 siRNA组的MMP-9 mRNA表达量与对照组相比显著降低,(P<0.05); MMP-9 siRNA组的FasL mRNA表达量与对照组相比差异无显著性意义(P>0.05)。2、转染后,MMP-9 siRNA组的MMP-9蛋白分泌表达与对照组中的表达量相比明显降低,(P<0.05); MMP-9 siRNA组细胞内的MMP-9蛋白表达与对照组中的表达量相比明显降低(P<0.05)。转染后,MMP-9 siRNA组的FasL蛋白分泌表达与对照组中的表达量相比明显降低,(P<0.05)；而MMP-9 siRNA组细胞内的FasL蛋白表达与对照组中的表达量相比明显增多,(P<0.05)。3、外源性MMP-9蛋白作用后,MMP-9 siRNA组及对照组中细胞外分泌的FasL蛋白表达均较作用前明显增多(P<0.05)；而MMP-9 siRNA组及对照组中细胞内的FasL蛋白表达均较作用前明显减少(P<0.05)。
结论
1、化学合成的MMP-9 siRNA能有效、特异性沉默TEV-1细胞株中的MMP-9基因。2、TEV-1细胞中MMP-9蛋白分泌表达影响细胞内、外FasL蛋白表达。3、外源性MMP-9蛋白也影响TEV-1细胞内、外FasL蛋白表达。
第三部分MMP-9在绒毛外滋养细胞致内皮细胞凋亡中的作用和机制的研究
目的
通过脂质体介导转染MMP-9 siRNA,探讨绒毛外滋养细胞基质金属蛋白酶-9(MMP-9)的表达对血管内皮细胞凋亡的影响。
方法
1、在transwell上室培养TEV-1细胞株,并以脂质体介导转染MMP-9 siRNA及其对照至TEV-1。2、在transwell下室培养EVC-304细胞株,使TEV-1和EVC-304非接触性共培养。3、共培养后收集下室细胞及上清液,流式细胞仪检测EVC-304细胞的凋亡率。4、单独培养EVC-304,给予外源性MMP-9,流式细胞仪检测不同时间段EVC-304的凋亡率。
结果
1、共培养体系中,MMP-9 siRNA组的滋养细胞所致内皮细胞凋亡率比对照组有明显降低(P<0.05)；在MMP-9 siRNA+MMP-9组,内皮细胞凋亡率较MMP-9 siRNA组明显增多(P<0.05)；对于对照+MMP-9组,内皮细胞凋亡率较对照组明显增多(P<0.05)。2、MMP-9直接单独作用于内皮细胞后,不同时间段的内皮细胞凋亡率无显著性差异(P<0.05)。
结论
1、绒毛外滋养细胞分泌MMP-9的改变导致其诱导内皮细胞凋亡的改变。2、滋养细胞分泌MMP-9致内皮细胞凋亡率改变,是通过MMP-9对滋养细胞分泌FasL蛋白的调控实现的。
Part one Study of expression of MMP-9 and FasL in placenta of preeclampsia
Objective:To investigate the involement of MMP-9 and FasL in the pathological mechanism of preeclampsia and the correlation between them.
Methods:The expression of MMP-9 and FasL of placenta tissue in 24 cases of normal term preganancy and 48 cases of preeclampsia women was determined by immunohistological method.
Results:
Expression of MMP-9 and FasL was mainly located in the cytoplasm and membrane of trophoblasts. Compared with control group, the expression of MMP-9 in the preeclampsia group was significantly lower(P<0.05), while the expression of FasL in the preeclampsia group was significantly higher than those of control group(P< 0.05). There was a significantly negative correlation between the expression of MMP-9 and FasL in placenta tissue(r=-0.700,P<0.05).
Conclusions:
1. Altered expression of MMP-9 and FasL in trophoblasts might influence the invasion of trophoblasts and artery remodeling, thus contribute to the pathogenesis of preeclampsia.
2. Trophoblast invasion might be associated with endothelial apoptosis, both of which were involved in the mechanism of preeclampsia.
Part two
Study of role and mechanism of MMP-9 of extravillous trophoblasts on FasL secretion
Objective:To investigate the release of FasL by regulation of MMP-9 secreted by extravillous trophoblasts(TEV-1), MMP-9siRNA was transfected into TEV-1 by lipofectamine.
Methods:1. MMP-9 siRNA was constructed and then transfected into TEV-1 cells by lipofectamine.2. After transfection, the level of MMP-9, FasL mRNA were assessed by real-time PCR, and the intracellular or extracellular level of these proteins were measured by ELISA.3. After administration of recombinant MMP-9, the intracellular or extracellular level of FasL was measured by ELISA.
Results:
1. The cells transfected with MMP-9 siRNA had a remarkable decrease in MMP-9 mRNA level as compared with those transfected with control siRNA(P<0.05), whereas FasL mRNA level between the two groups had no significant changes(P>0.05).
2. MMP-9 siRNA caused a significant decrease in the secretion of MMP-9(P<0.05), whereas control siRNA did not alter the secretion. There was a decrease expression of intracellular MMP-9 in MMP-9 siRNA transfected cells when compared with cells transfected with control siRNA(P<0.05).The level of sFasL were significantly reduced in cells transfected with MMP-9 siRNA as compared with that in cells transfected with control siRNA(P<0.05). Increased expression of intracellular FasL was detected in cells transfected with MMP-9 siRNA as compared with that in cells with control siRNA(P<0.05).
3. sFasL release was markedly recovered by adding exogenous MMP-9 to MMP-9 siRNA transfected cells(P<0.05). Following recombinant MMP-9 added to control siRNA, a significant increase of sFasL was present with exogenous MMP-9 treatment(P<0.05). Expression of intracellular FasL was recovered to control level after adding exogenous MMP-9 to MMP-9 siRNA treated cells(P<0.05). Exogenous MMP-9 to control siRNA was observed to cause significant decrease of intracellular FasL expression(P<0.05).
Conclusions:
1. MMP-9 siRNA efficiently and specifically degraded MMP-9 mRNA in TEV-1 cells.
2. MMP-9 secreted by TEV-1 cells regulated both secreted and soluble FasL protein.
3. Recombinant MMP-9 effected both secreted and soluble FasL protein in TEV-1 cells.
Part three
Study of role and mechanism of MMP-9 of extravillous trophoblasts on endothelial apoptosis
Objective:To investigate the involvement of MMP-9 in trophoblasts-induced endothelial apoptosis, MMP-9siRNA was transfected into extravillous trophoblasts (TEV-1) by lipofectamine.
Methods:MMP-9siRNA was transfected into extravillous trophoblasts (TEV-1) by lipofectamine. Then trophoblasts transfected with MMP-9siRNA or control siRNA were cocultured with endothelial cells respectively in a transwell system. The apoptosis of endothelial cells were detected by flow cytometry. Besides, EVC-304 cells were cultured under MMP-9 for different period of time to observe whether MMP-9 has direct apoptosis effect on EVC-304 cells.
Results:
1. The percentage of cells externalizing phosphatidylserine, quantified by flow cytometry, showing that the level of endothelial apoptosis were significantly decreased when cocultured with trophoblasts transfected with MMP-9 siRNA, as compared with that when cocultured with trophoblasts transfected with control siRNA(P<0.05). Yet, the apoptosis level was recovered to control level by adding MMP-9 back to MMP-9 silencing cells(P<0.05). It showed MMP-9 administration(5ng/mL) of TEV-1 cells caused increased endothelial apoptosis(P<0.05).
2. We also studied whether MMP-9 alone, in addition to FasL, directly induces endothelial apoptosis. Apoptosis effect was investigated after stimulation of the cultures with MMP-9 (5ng/mL) for 6,12, or 24 hours. No difference was found as compared with control(P>0.05).
Conclusions:
1. MMP-9 secreted by extravillous trophoblasts induced endothelial apopotosis.
2. MMP-9 alone has no direct apoptosis effect on endothelial cells, and MMP-9 secreted by trophoblasts contributes to endothelial apoptosis via extracellular release of soluble FasL.
目的
探讨MMP-9和FasL在子痫前期发病机制中的作用及两者间的关联。
方法
采用免疫组织化学法检测48例子痫前期孕妇(重度子痫前24例,轻度子痫前期24例)及24例正常晚期妊娠孕妇胎盘中MMP-9和FasL的表达定位及强度。
结果
MMP-9主要表达于胎盘合体滋养细胞细胞质和细胞膜内,FasL主要表达于胎盘合体滋养细胞细胞质和细胞膜内。轻、重度子痫前期组MMP-9表达水平明显低于正常晚孕组(P<0.05)。轻、重度子痫前期组FasL表达水平明显高于正常晚孕组(P<0.05)。胎盘组织中MMP-9与FasL表达水平呈负相关(r=-0.700,P<0.05)。
结论
1、子痫前期胎盘滋养细胞中MMP-9与FasL表达异常,使胎盘形成时滋养细胞入侵减少及血管重塑障碍,可能与子痫前期的发病机制有关。
2、子痫前期胎盘滋养细胞中MMP-9与FasL的表达水平呈负相关,可能滋养细胞的侵入与其致内皮细胞凋亡作用之间存在关联,共同参与子痫前期的发生。
第二部分绒毛外滋养细胞中MMP-9表达对FasL分泌的作用和机制的研究
目的
通过脂质体转染MMP-9siRNA,探讨绒毛外滋养细胞株TEV-1中基质金属蛋白酶-9(MMP-9)对可溶性Fas配体(sFasL)表达的调控。
方法
1、化学合成MMP-9siRNA,通过脂质体转染绒毛外滋养细胞株TEV-1。2、RealTime RT-PCR、ELISA检测MMP-9siRNA转染效率,ELISA检测细胞内、外FasL蛋白表达的变化。3、给予外源性MMP-9,ELISA检测细胞内、外FasL蛋白表达的变化。
结果
1、转染后,MMP-9 siRNA组的MMP-9 mRNA表达量与对照组相比显著降低,(P<0.05); MMP-9 siRNA组的FasL mRNA表达量与对照组相比差异无显著性意义(P>0.05)。2、转染后,MMP-9 siRNA组的MMP-9蛋白分泌表达与对照组中的表达量相比明显降低,(P<0.05); MMP-9 siRNA组细胞内的MMP-9蛋白表达与对照组中的表达量相比明显降低(P<0.05)。转染后,MMP-9 siRNA组的FasL蛋白分泌表达与对照组中的表达量相比明显降低,(P<0.05)；而MMP-9 siRNA组细胞内的FasL蛋白表达与对照组中的表达量相比明显增多,(P<0.05)。3、外源性MMP-9蛋白作用后,MMP-9 siRNA组及对照组中细胞外分泌的FasL蛋白表达均较作用前明显增多(P<0.05)；而MMP-9 siRNA组及对照组中细胞内的FasL蛋白表达均较作用前明显减少(P<0.05)。
结论
1、化学合成的MMP-9 siRNA能有效、特异性沉默TEV-1细胞株中的MMP-9基因。2、TEV-1细胞中MMP-9蛋白分泌表达影响细胞内、外FasL蛋白表达。3、外源性MMP-9蛋白也影响TEV-1细胞内、外FasL蛋白表达。
第三部分MMP-9在绒毛外滋养细胞致内皮细胞凋亡中的作用和机制的研究
目的
通过脂质体介导转染MMP-9 siRNA,探讨绒毛外滋养细胞基质金属蛋白酶-9(MMP-9)的表达对血管内皮细胞凋亡的影响。
方法
1、在transwell上室培养TEV-1细胞株,并以脂质体介导转染MMP-9 siRNA及其对照至TEV-1。2、在transwell下室培养EVC-304细胞株,使TEV-1和EVC-304非接触性共培养。3、共培养后收集下室细胞及上清液,流式细胞仪检测EVC-304细胞的凋亡率。4、单独培养EVC-304,给予外源性MMP-9,流式细胞仪检测不同时间段EVC-304的凋亡率。
结果
1、共培养体系中,MMP-9 siRNA组的滋养细胞所致内皮细胞凋亡率比对照组有明显降低(P<0.05)；在MMP-9 siRNA+MMP-9组,内皮细胞凋亡率较MMP-9 siRNA组明显增多(P<0.05)；对于对照+MMP-9组,内皮细胞凋亡率较对照组明显增多(P<0.05)。2、MMP-9直接单独作用于内皮细胞后,不同时间段的内皮细胞凋亡率无显著性差异(P<0.05)。
结论
1、绒毛外滋养细胞分泌MMP-9的改变导致其诱导内皮细胞凋亡的改变。2、滋养细胞分泌MMP-9致内皮细胞凋亡率改变,是通过MMP-9对滋养细胞分泌FasL蛋白的调控实现的。
Part one Study of expression of MMP-9 and FasL in placenta of preeclampsia
Objective:To investigate the involement of MMP-9 and FasL in the pathological mechanism of preeclampsia and the correlation between them.
Methods:The expression of MMP-9 and FasL of placenta tissue in 24 cases of normal term preganancy and 48 cases of preeclampsia women was determined by immunohistological method.
Results:
Expression of MMP-9 and FasL was mainly located in the cytoplasm and membrane of trophoblasts. Compared with control group, the expression of MMP-9 in the preeclampsia group was significantly lower(P<0.05), while the expression of FasL in the preeclampsia group was significantly higher than those of control group(P< 0.05). There was a significantly negative correlation between the expression of MMP-9 and FasL in placenta tissue(r=-0.700,P<0.05).
Conclusions:
1. Altered expression of MMP-9 and FasL in trophoblasts might influence the invasion of trophoblasts and artery remodeling, thus contribute to the pathogenesis of preeclampsia.
2. Trophoblast invasion might be associated with endothelial apoptosis, both of which were involved in the mechanism of preeclampsia.
Part two
Study of role and mechanism of MMP-9 of extravillous trophoblasts on FasL secretion
Objective:To investigate the release of FasL by regulation of MMP-9 secreted by extravillous trophoblasts(TEV-1), MMP-9siRNA was transfected into TEV-1 by lipofectamine.
Methods:1. MMP-9 siRNA was constructed and then transfected into TEV-1 cells by lipofectamine.2. After transfection, the level of MMP-9, FasL mRNA were assessed by real-time PCR, and the intracellular or extracellular level of these proteins were measured by ELISA.3. After administration of recombinant MMP-9, the intracellular or extracellular level of FasL was measured by ELISA.
Results:
1. The cells transfected with MMP-9 siRNA had a remarkable decrease in MMP-9 mRNA level as compared with those transfected with control siRNA(P<0.05), whereas FasL mRNA level between the two groups had no significant changes(P>0.05).
2. MMP-9 siRNA caused a significant decrease in the secretion of MMP-9(P<0.05), whereas control siRNA did not alter the secretion. There was a decrease expression of intracellular MMP-9 in MMP-9 siRNA transfected cells when compared with cells transfected with control siRNA(P<0.05).The level of sFasL were significantly reduced in cells transfected with MMP-9 siRNA as compared with that in cells transfected with control siRNA(P<0.05). Increased expression of intracellular FasL was detected in cells transfected with MMP-9 siRNA as compared with that in cells with control siRNA(P<0.05).
3. sFasL release was markedly recovered by adding exogenous MMP-9 to MMP-9 siRNA transfected cells(P<0.05). Following recombinant MMP-9 added to control siRNA, a significant increase of sFasL was present with exogenous MMP-9 treatment(P<0.05). Expression of intracellular FasL was recovered to control level after adding exogenous MMP-9 to MMP-9 siRNA treated cells(P<0.05). Exogenous MMP-9 to control siRNA was observed to cause significant decrease of intracellular FasL expression(P<0.05).
Conclusions:
1. MMP-9 siRNA efficiently and specifically degraded MMP-9 mRNA in TEV-1 cells.
2. MMP-9 secreted by TEV-1 cells regulated both secreted and soluble FasL protein.
3. Recombinant MMP-9 effected both secreted and soluble FasL protein in TEV-1 cells.
Part three
Study of role and mechanism of MMP-9 of extravillous trophoblasts on endothelial apoptosis
Objective:To investigate the involvement of MMP-9 in trophoblasts-induced endothelial apoptosis, MMP-9siRNA was transfected into extravillous trophoblasts (TEV-1) by lipofectamine.
Methods:MMP-9siRNA was transfected into extravillous trophoblasts (TEV-1) by lipofectamine. Then trophoblasts transfected with MMP-9siRNA or control siRNA were cocultured with endothelial cells respectively in a transwell system. The apoptosis of endothelial cells were detected by flow cytometry. Besides, EVC-304 cells were cultured under MMP-9 for different period of time to observe whether MMP-9 has direct apoptosis effect on EVC-304 cells.
Results:
1. The percentage of cells externalizing phosphatidylserine, quantified by flow cytometry, showing that the level of endothelial apoptosis were significantly decreased when cocultured with trophoblasts transfected with MMP-9 siRNA, as compared with that when cocultured with trophoblasts transfected with control siRNA(P<0.05). Yet, the apoptosis level was recovered to control level by adding MMP-9 back to MMP-9 silencing cells(P<0.05). It showed MMP-9 administration(5ng/mL) of TEV-1 cells caused increased endothelial apoptosis(P<0.05).
2. We also studied whether MMP-9 alone, in addition to FasL, directly induces endothelial apoptosis. Apoptosis effect was investigated after stimulation of the cultures with MMP-9 (5ng/mL) for 6,12, or 24 hours. No difference was found as compared with control(P>0.05).
Conclusions:
1. MMP-9 secreted by extravillous trophoblasts induced endothelial apopotosis.
2. MMP-9 alone has no direct apoptosis effect on endothelial cells, and MMP-9 secreted by trophoblasts contributes to endothelial apoptosis via extracellular release of soluble FasL.
引文
1. Robson SC, Simpson H, Ball L, et al. Punch biopsy of the human placental bed. Am J Obstet Gynecol,2002,187:1349-1355
2. Pijnenborg R, Bland JM, Robertson WB, et al. The pattern of interstitial trophoblast invasion in early human pregnancy. Placenta,1981,2:303-316
3. Pijnenborg R. The placental bed. Hypertens Pregnancy,1996,15:7-23
4. Pijnenborg R, Bland JM, Robertson WB,et al. Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta,1983,4:397-414
5. Gerretsen G, Huisjes HJ, Elema JD. Morphological changes of spiral arteries in the placental bed in relation to pre-eclampsia and fetal growth retardation.Br J Obstet Gynaecol,1981,88:876-881
6. Pijnenborg R, Dixon G, Robertson WB,et al. The arterial migration of trophoblast in the uterus of the golden hamster. J Reprod Fertil,1974,40:269-280
7. Robson SC, Ball E, Lyall F,et al. Endovascular trophoblast invasion and spiral artery transformation:the "two wave" theory revisited. Placenta 2001,22:25
8. Brosens IA, Robertson WB and Dixon HG. The role of the spiral arteries in the pathogenesis of pre-eclampsia. Obstetrics and gynecology annual,1972,1:177-191
9. Pijnenborg R, Anthony J, Davey DA,et al. Placental bed spiral arteries in the hypertensive disorders of pregnancy. Br J Obstet Gynaecol,1991,98:648-655
10. Meekins JW, Pijnenborg R, Hanssens M, et al. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol,1994,101:669-674
11. Khong TY, De Wolf F, Robertson WB,et al. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol,1986,93:1049-1059
12. Lyall F, Simpson H, Robson SC, et al. Transforming growth factor β expression in human placenta and placental bed in normal pregnancy, preeclampsia and fetal growth restriction.Am J Pathol,2001,159:1827-1838
13. Lyall. Cell adhesion molecules:their role in pregnancy.Fetal Matern Med Rev,1998,10: 21-44
14. Huppert B, Kertschanska S, Demir A,et al. 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
15. Lala PK, Hamilton GS. Growth factors, proteases and protease inhibitors in the maternal-fetal dialogue.Placenta,1996,17:545-555
16. DiFederico E, Genbacev O,Fisher FJ.Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall.Am J Pathol,1999,155: 293-301
17. Kadyrov M,Schmitz C, Black S. Pre-eclampsia and maternal anaemia display reduced apoptosis and opposite invasive phenotypes of extravillous trophoblast. Placenta,2003, 24:540-548
18. Challier JC,Uzan S. The human placenta and its pathologies:focus on oxygen.Med Sci,2003,19:1111-1120
19. Rajakumar A, Conrad KP.Expression, ontogeny, and regulation of hypoxia-inducible transcription factors in the human placenta. Biol Reprod,2000,63:559-569
20. Moffett A,.NK cells and reproduction.Placenta,2004,25:K4
21. Lyall F. Development of the uteroplacental circulation:the role of carbon monoxide and nitric oxide in trophoblast invasion and spiral artery transformation. Microsc Res Tech,2003,60:402-411
22. C:\2010.3\ScienceDirect-Placenta Priming and remodelling of human placental bed spiral arteries during pregnancy-A Review.htm-bbib40Lyall F, Robson SC, Bulmer JN. Human trophoblast invasion and spiral artery transformation:the role of nitric oxide.Am J Pathol,1999,154:1105-1114
23. Lyall F, Barber A, Myatt L, et al. Hemeoxygenase expression in human placenta and placental bed implies a role in regulation of trophoblast invasion and placental function.FASEB J,2000,14:208-219
24. Maines MD. Heme oxygenase:function, multiplicity, regulatory mechanisms and clinical applications.FASEB J,1988,2:2257-2568
25. Maines MD.Carbon monoxide:an emerging regulator of cGMP in the brain.Mol Cell Neurosci,1993,4:389-397
1. Sibai BN, Caritis SN, Thom E, et al.Prevention of preeclampsia with low-dose aspirin in health nulliparous pregnant women. N Engl J Med,1993,329:1213-1218
2. Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med,1997,337:69-76
3. Walker JJ. Preeclampsia. Lancet,2000,356:1260-1265
4. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. Lancet,2001,357: 53-56
5. Goldenberg RL, Rouse DJ. Prevention of premature birth. N Engl J Med,1998,339: 313-320
6. Duley L. Maternal mortality associated with hypertensive disorders of pregnancy in Africa, Asia, Latin America and the Caribbean. Br J Obstet Gynaecol,1992,99: 547-553
7. Starzyk KA, Pijnenborg R, Salafia CM. Decidual and vascular pathophysiology in pregnancy compromise. Semin Reprod Endocrinol.1999,17(1):63-72
8. Lacroix MC, Guibourdenche J, Fournier T,et al. Stimulation of human trophoblast invasion by placental growth hormone. Endocrinology,146:2434-2444
9. Pollheimer J, Knofler M. Signalling pathways regulating the invasive differentiation of human trophoblasts, a review. Placenta,2005,26(Suppl A):S21-S30
10. Liotta LA. Tumour invasion and metastases, role of the basement membrane. Warner-Lambert Parke-Davis Award lecture. Am J Pathol,117:339-348
11. Bischof P. Endocrine, paracrine and autocrine regulation of trophoblastic metalloproteinases. Early Pregnancy,2001,5:30-31
12. Staff AC. An introduction to cell migration and invasion. Scand J Clin Lab Invest,2001, 61:257-268
13. Staff AC, Ranheim T, Henriksen T, et al.8-iso prostaglandin freduces trophblast invasion and matrix metalloproteinase activity. Hypertension,2000,35(6):1307-20
14. Berthold H, Kertschanska S. Immunohistochemistry of matrix metalloproteinase(MMP), their substrates and their inhibitors(TIMP) during trophoblast invasion in human placenta. Cell Tissue Res,1998,291:133-148
15. Naicker T, Khedun SM, Moodley J,et al. Quantitative analysis of trophoblast invasion in preeclampsia. Acta Obstet Gynecol Scand,2003,82:722-729
16. Sandra VA, Guy JW, Philip RD, et al. Uterine spiral artery remodeling involves endothelial apoptosis induced by extravillous trophoblasts through Fas/FasL interactions. Arteriosclerosis, Thrombosis, and Vascular Biology,2005,25:102-108
1. Pijnenborg R, Bland JM, Robertson WB, et al.The pattern of interstitial trophoblast invasion in early human pregnancy.Placenta,1981(2):303-316
2. Pijnenborg R, Bland JM, Robertson WB, et al. Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta,1983(4):397-414
3. Roberston WB, Khong TY, Brosens I, et al. The placental bed biopsy:review from three European centres. Am J Obstet Gynecol,1986(155):401-412
4. Pijnenborg R, Dixon G, Robertson WB et al.The arterial migration of trophoblast in the uterus of the golden hamster. J Reprod Fertil,1974(40):269-280
5. Robson SC, Ball E, Lyall F, et al. Endovascular trophoblast invasion and spiral artery transformation:the "two wave" theory revisited. Placenta,2001(22):A25
6. Christopher WR, Ian LS. Latest advances in understanding Preeclampsia. Science,2005, 308:1592-1594
7. Pijnenborg R, Dixon G, Robertson WB, et al. Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy. Placenta,1980,1:3-19
8. Enders AC, Blankenship TN. Modification of endometrial arteries during invasion by cytotrophoblast cells in the pregnant macaque. Acta Anat (Basel),1997,159:169-193
9. Ashton SV, Whitley GS, Dash PR, et al. Uterine spiral artery remodeling involves endothelial apoptosis induced by extravillous trophoblasts through Fas/FasL interactions. Arterioscler Thromb Vasc Biol,2005,25:102-108
10. Cartwright JE, Kenny LC, Dash PR, et al. Trophoblast invasion of spiral arteries:a novel in vitro model. Placenta,2002,23:232-235
11. Brosens IA, Robertson WB, Dixon HG The role of the spiral arteries in the pathogenesis of pre-eclampsia. Obstetrics and gynecology annual,1972(1):177-191
12. Fumio T, Rumiko N, Teruo A, et al. Proapoptotic effect of Proteolytic Activation of Matrix Metalloproteinases by streptococcus pyogenes Thiol Proteinase. Infect Immun,2004,72(8):4836-4847
1. Gordon MC. Maternal physiology. Normal and problem pregnancies,2007:55-84
2. Clapp JF, Capeless E. Cardiovascular function before, during, and after the first and subsequent pregnancies. Am J Cardiol,1997,80:1469-1473
3. Khong TY, De Wolf F, Robertson WB, et al. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol,1986,93:1049-1059
4. Khong TY, Liddell HS, Robertson WB. Defective haemochorial placentation as a cause of miscarriage. Br J Obstet Gynaecol,1987,94:649-655
5. Meekins JW, Pijnenborg R, Hanssens M, et al. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol.1994,101:669-674
6. Kim Y.M, Chaiworapongsa T, Gomez R, et al. Failure of the physiologic transformation of the spiral arteries in the placental bed in preterm premature rupture of membranes. Am J Obstet Gynecol,2002,187:1137-1142
7. Jauniaux E, Ramsay B, Campbell S. Ultrasonographic investigation of placental morphologic characteristics and size during the second trimester of pregnancy. Am J Obstet Gynecol,1994,170:130-137
8. Viero S, Chaddha V, Alkazaleh F, et al. Prognostic value of placental ultrasound in pregnancies complicated by absent end-diastolic flow velocity in the umbilical arteries. Placenta,2004,25:735-741
9. Toal M, Chan C, Fallah S, et al. Usefulness of a placental profile in high-risk pregnancies. Am J Obstet Gynecol,2007,196(363):el-e7
10. Crocker IP, Brownbill P, Hutchinson ES, et al. Irregular intervillous haemodynamics in the placental pathophysiology of pre-eclampsia. J Soc Gynecol Investig,2006,3(Suppl.): 232A
11. Burton GJ, Jones CJ. Syncytial knots, sprouts, apoptosis and trophoblast deportation from the human placenta. Taiwan J Obstet Gynecol,2009,48:28-37
12. Hung TH, Skepper JN, Charnock-Jones DS et al. Hypoxia/reoxygenation:a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circ Res,2002,90:1274-1281
13. Hung TH, Charnock-Jones DS, Skepper JN, et al. Secretion of tumour necrosis factor-a from human placental tissues induced by hypoxia-reoxygenation causes endothelial cell activation in vitro:a potential mediator of the inflammatory response in preeclampsia. Am J Pathol,2004,164:1049-1061
14. Soleymanlou N, Wu Y, Wang JX, et al. A novel Mtd splice isoform is responsible for trophoblast cell death in pre-eclampsia. Cell Death Differ,2005,12:441-452
15. Redman CW, Sacks GP, Sargent IL. Preeclampsia:an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol,1999,180:499-506
1. O'Brien SN, Welter BH,Price TM. Presence of leptin in breast cell lines and breast tumours. Biochem Biophys Res Commun,1999,259:695-698
2. Strickland S, Richards WG Invasion of the trophoblasts.Cell,1992,71:355-357
3. Genbacev O, Zhou Y, Ludlow JW, et al. Regulation of human placental development by oxygen tension. Science,1997,277:1669-1672
4. Redman CW. Cytotrophoblasts, masters of disguise.Nat Med,1997,3:610-611
5. Even-Ram S, Uziely B, Cohen P,et al. Thrombin receptor overexpression in malignant and physiological invasion processes.Nat Med,1998,4:909-914
6. Mullen CA. Review, analogies between trophoblastic and malignant cells. Am J Reprod Immunol,1998:39:41-49
7. Redman CW, Sargent IL and Starkey PM. The Human Placenta. Backwell Scientific Publications, Oxford,1993
8. Cross JC, Werb Z and Fisher. Implantation and the placenta, key pieces of the development puzzle. Science,1994,266:1508-1518
9. Loke YW and King A.Human Implantation. Cambridge University Press, Cambridge,1995
10. Lacroix MC, Guibourdenche J, Fournier T, et al. Stimulation of human trophoblast invasion by placental growth hormone. Endocrinology,2005,146:2434-2444
11. Pollheimer J,Knofler M. Signalling pathways regulating the invasive differentiation of human trophoblasts, a review. Placenta,2005,26(Suppl A):S21-S30
12. Poste QFidler IJ. The pathogenesis of cancer metastasis. Nature,1980,283;139-146
13.Bischof P,Campana A. A putative role for oncogenes in trophoblast invasion? Hum Reprod,2000,15(Suppl 6):51-58
14. Staff AC. An introduction to cell migration and invasion. Scand J Clin Lab Invest,2001, 61:257-268
15.Hahn WC,Weinberg RA.Modelling the molecular circuitry of cancer. Nat Rev Cancer,2002,2:331-341
16. Ullrich A, Coussens L, Hayflick JS, et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature,1984,309:418-425.
17. Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases, targets for cancer therapy. Nat Rev Cancer,2004,4:361-370
18. Hynes NE. ERBB receptors and cancer, the complexity of targeted inhibitors. Nat Rev Cancer,2005,5:341-354
19. Fulop V, Mok SC, Genest DR, et al. c-myc, c-erbB-2, c-fms and bcl-2 oncoproteins. Expression in normal placenta, partial and complete mole, and choriocarcinoma. J Reprod Med,1998,43:101-110
20. Doneda L, Bulfamante G, Grimoldi MG, et al. Localization of fos, jun, kit and SCF mRNA in human placenta throughout gestation using in situ RT-PCR. Early Pregnancy,1997,3:265-271
21.Hantschel O,Superti-Furga G. Regulation of the c-Ab1 and Bcr-Ab1 tyrosine kinases. Nat Rev Mol Cell Biol,2004,5:33-44
22. Takai N, Ueda T, Narahara H et al. Expression of c-Ets1 protein in normal human placenta. Gynecol Obstet Invest,2005,61:15-20
23. Bamberger AM, Bamberger CM, Aupers S,et al. Expression pattern of the activating protein-1 family of transcription factors in the human placenta. Mol Hum Reprod,2004,10:223-228
24. Montell DJ.Anchors away! Fos fosters anchor-cell invasion. Cell 2005,121:816-817
25. Sherwood DR, Butler JA, Kramer JM, et al. FOS-1 promotes basement-membrane removal during anchor-cell invasion in C. elegans. Cell,2005,121:951-962
26. Dang CV, O'Donnell KA, Juopperi T. The great MYC escape in tumourigenesis. Cancer Cell2005,8:177-178
27. Paumelle R, Tulasne D, Kherrouche Z, et al. Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. Oncogene,2002,21:2309-2319
28. Takai N, Ueda T, Narahara H et al. Expression of c-Etsl protein in normal human placenta. Gynecol Obstet Invest,2005,61:15-20
29. Downward J.Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer,2003,3:11-22
30. Malumbres M, Barbacid M. RAS oncogenes, the first 30 years. Nat Rev Cancer,2003, 3:459-465
31. Chakraborty C, Gleeson LM, McKinnon T et al. Regulation of human trophoblast migration and invasiveness. Can J Physiol Pharmacol,2002,80:116-124
32. Tseng JJ, Chou MM, Hsieh YT, et al.Differential expression of vascular endothelial growth factor, placenta growth factor and their receptors in placentae from pregnancies complicated by placenta accreta. Placenta,2006,27:70-78
33.Bischof P, Meisser A, Campana A. Paracrine and autocrine regulators of trophoblast invasion—a review. Placenta,2000,21(Suppl A)z;S55-S60
34. Bjorn SF, Hastrup N, Larsen JF, et al. Messenger RNA for membrane-type 2 matrix metalloproteinase, MT2-MMP, is expressed in human placenta of first trimester. Placenta,2000,21z:170-176
35. Isaka K, Usuda S, Ito H, et al. Expression and activity of matrix metalloproteinase 2 and 9 in human trophoblasts. Placenta,2003,24:53-64
36. Haimov-Kochman R, Friedmann Y, Prus D, et al. Localization of heparanase in normal and pathological human placenta. Mol Hum Reprod,2002,8:566-573
37. Chou CS, Beristain AG, MacCalman CD et al. Cellular localization of gonadotropin-releasing hormone (GnRH) I and GnRH II in first-trimester human placenta and decidua. J Clin Endocrinol Metab,2004,89:1459-1466
38.Ozturk M, Brown N, Milunsky A et al. Physiological studies of human chorionic gonadotropin and free subunits in the amniotic fluid compartment compared to those in maternal serum. J Clin Endocrinol Metab,1988,67:1117-1121
39. Marcillac I, Troalen F, Bidart JM, et al. Free human chorionic gonadotropin beta subunit in gonadal and nongonadal neoplasms. Cancer Res,1992,52:3901-3907
40. Malatesta M, Mannello F, Luchetti F, et al. Prostate-specific antigen synthesis and secretion by human placenta, a physiological kallikrein source during pregnancy. J Clin Endocrinol Metab,2000,85:317-321
41.Briese J, Oberndorfer M, Patschenik C, et al.Osteopontin is colocalized with the adhesion molecule CEACAM1 in the extravillous trophoblast of the human placenta and enhances invasion of CEACAM1-expressing placental cells. J Clin Endocrinol Metab,2005,90:5407-5413
42. Chen ME, Lin SH, Chung LW, et al. Isolation and characterization of PAGE-1 and GAGE-7. New genes expressed in the LNCaP prostate cancer progression model that share homology with melanoma-associated antigens. J Biol Chem,1998, 273:17618-17625
43. De Backer O, Arden KC, Boretti M, et al.Characterization of the GAGE genes that are expressed in various human cancers and in normal testis. Cancer Res,1999, 59:3157-3165
44. Kwon S, Kang SH, Ro J, et al. The melanoma antigen gene as a surveillance marker for the detection of circulating tumour cells in patients with breast carcinoma. Cancer,2005, 104:251-256
45. Lotem J, Netanely D, Domany E,et al. Human cancers overexpress genes that are specific to a variety of normal human tissues. Proc Natl Acad Sci USA,2005, 102:18556-18561
46. Lewis TS, Shapiro PS,Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res,1998,74:49-139
47. Pollheimer J, Knofler M. Signalling pathways regulating the invasive differentiation of human trophoblasts, a review. Placenta,2005,26(Suppl A):S21-S30
48. Kita N, Mitsushita J, Ohira S, et al. Expression and activation of MAP kinases, ERK1/2, in the human villous trophoblasts. Placenta,2003,24:164-172
49. Vivanco I,Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer,2002,2:489-501
50. Toker A, Yoeli-Lerner M. Akt signaling and cancer:surviving but not moving on. Cancer Res,2006,66:3963-3966
51. Vivanco I, Sawyers CL.The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer,2002,2:489-501
52. Cully M, You H, Levine AJ. Beyond PTEN mutations:the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer,2006,6:184-192
53.Fingar DC, Blenis J. Target of rapamycin (TOR):an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene,2004, 23:3151-3171
54. Duan C, Bauchat JR,Hsieh T. Phosphatidylinositol 3-kinase is required for insulin-like growth factor-I-induced vascular smooth muscle cell proliferation and migration. Circ Res,2000,86:15-23
55. Cartwright JE, Tse WK, Whitley GS. Hepatocyte growth factor induced human trophoblast motility involves phosphatidylinositol-3-kinase, mitogen-activated protein kinase, and inducible nitric oxide synthase. Exp Cell Res,2002,279:219-226
56. Qiu Q, Yang M, Tsang BK,et al. Both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signalling are required in epidermal growth factor-induced human trophoblast migration. Mol Hum Reprod,2004,10:677-684
57. Gabarra-Niecko V, Schaller MD,Dunty JM. FAK regulates biological processes important for the pathogenesis of cancer. Cancer Metastasis Rev,2003,22:359-374
58. Ilic D, Genbacev O, Jin F, Caceres E, et al.Plasma membrane-associated pY397FAK is a marker of cytotrophoblast invasion in vivo and in vitro. Am J Pathol,2001, 159:93-108
59. MacPhee DJ, Mostachfi H, Han R,et al. Focal adhesion kinase is a key mediator of human trophoblast development. Lab Invest,2001,81:1469-1483
60. Goode BL, Drubin DG, Barnes G. Functional cooperation between the microtubule and actin cytoskeletons. Curr Opin Cell Biol,2000,12:63-71
61. Shiokawa S, Iwashita M, Akimoto Y, et al. Small guanosine triphospatase RhoA and Rho-associated kinase as regulators of trophoblast migration. J Clin Endocrinol Metab,2002,87:5808-5816
62. Hanahan D,Weinberg RA.The hallmarks of cancer. Cell,2000,100:57-70
63. Birchmeier C, Birchmeier W, Gherardi E et al. Met, metastasis, motility and more. Nat Rev Mol Cell Biol,2003,4:915-925
64. Olsson AK, Dimberg A, Kreuger J et al. VEGF receptor signalling-in control of vascular function. Nat Rev Mol Cell Biol,2006,7:359-371
65. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia, role of the HIF system. Nat Med,2003,9:677-684
66. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell,2000,100:57-70
67. Khandwala HM, McCutcheon IE, Flyvbjerg A,et al. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev,2000,21:215-244
68. Chakraborty C, Gleeson LM, McKinnon T,et al.Regulation of human trophoblast migration and invasiveness. Can J Physiol Pharmacol,2000,80:116-124
69. Irish JM, Kotecha N, Nolan GP. Mapping normal and cancer cell signalling networks: towards single-cell proteomics. Nat Rev Cancer,2006,6:146-155
70. Guo W, Giancotti FG Integrin signalling during tumour progression. Nat Rev Mol Cell Biol,2004,5:816-826
71. Hood JD, Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer,2002,2:91-100
72. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3'kinase/AKT pathways. Oncogene,2005,24:7443-7454
73. Cohen M, Meisser A, Bischof P. Metalloproteinases and human placental invasiveness. Placenta,2006,27:783-793
74. Cully M, You H, Levine AJ et al. Beyond PTEN mutations:the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006,6:184-192
75. Bancroft CC, Chen Z, Yeh J, et al. Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-kappaB and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines. Int J Cancer,2002,99:538-548
76. Dempsey LA, Plummer TB, Coombes SL et al. Heparanase expression in invasive trophoblasts and acute vascular damage. Glycobiology,2000,10:467-475
77. Sinkovics JG, Horvath JC. Human natural killer cells, a comprehensive review. Int J Oncol,2005,27:5-47
78. Knofler M, Sooranna SR, Daoud G,et al. Trophoblast signalling, knowns and unknowns—a workshop report. Placenta,2005,26(Suppl A):S49-S51
1. Sibai BN, Caritis SN, Thom E, et al. Prevention of preeclampsia with low-dose aspirin in health. Nulliparous pregnant women. N Engl J Med,1993,329:1213-1218
2. Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med,1997,337:69-76
3. Walker JJ. Preeclampsia. Lancet,2000,356:1260-1265
4. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. Lancet,2001, 357:53-56
5. Von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy,2003,22:143-148
6. Huppertz B, Herrler A. Regulation of proliferation and apoptosis during development of the preimplantation embryo and the placenta. Birth Defects Res C Embryo Today, 2005,75:249-261
7. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia:current concepts. Am J Obstet Gynecol,1998,179:1359-1375
8. Kenny L, Baker PN. Maternal pathophysiology in pre-eclampsia. Baillieres Best Pract Res Clin Obstet Gynaecol,1999,13:59-75
9. Sekotory A, Ahmed M. Pre-eclampsia:hypotheses. J R Soc Health,2001,121:76-78
10.Wilson ML, Goodwin TM, Pan VL, et al. Molecular epidemiology of preeclampsia. Obstet Gynecol Surv,2003,58:39-66
11. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science, 2005,308:1592-1594
12.Knight M, Redman CW, Linton EA, et al. Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. Br J Obstet Gynaecol, 1998,105:632-640
13.Jauniaux E, Watson AL, Hempstock J, et al. 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
14.Huppertz B, Sammar M, Chefetz I, et al. Longitudinal determination of serum PP13 during development of preeclampsia. Fetal Diagn Therapy,2008,24(3):230-236
15.Huppertz B, Kingdom JC. Apoptosis in the trophoblast-role of apoptosis in placental morphogenesis. J Soc Gynecol Investig,2004,11:353-362
16.Huppertz B, Frank HG, Kingdom JC, et al. Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta. Histochem Cell Biol,1998,110: 495-508
17.Benirschke K, Kaufmann P, Baergen R. Pathology of the Human Placenta,5th ed., Springer New York,2006
18.Ikle FA. Trophoblastzellen im stromenden Blut. Schweiz Med Wochenschr,1964,91: 934-945
19.Goswami D, Tannetta DS, Magee LA, et al. Excess syncytiotrophoblast microparticle shedding is a feature of early-onset pre-eclampsia, but not normotensive intrauterine growth restriction. Placenta,2006,27:56-61
20.Freire-de-Lima CG, Xiao YQ, Gardai SJ, et al. Apoptotic cells, through transforming growth factor-beta, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. J Biol Chem, 2006,281:38376-38384
21.Krysko DV, D'Herde K, Vandenabeele P. Clearance of apoptotic and necrotic cells and its immunological consequences. Apoptosis,2006,11:1709-1726
22.Formigli L, Papucci L, Tani A, Schiavone N, et al. Aponecrosis:morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis. J Cell Physiol,2000,182:41-49
23. Gupta AK, Rusterholz C, Huppertz B, et al. A comparative study of the effect of three different syncytiotrophoblast microparticles preparations on endothelial cells. Placenta, 2005,26:59-66
24. Gaunt M, Ockleford CD. Microinjection of human placenta,Ⅱ:biologicalapplication. Placenta,1986,7:325-31
25.Burton GJ, Jauniaux E. Sonographic, stereological and Doppler flow velocimetric assessments of placental maturity.Br J Obstet Gynaecol,1995,102:818-25
26.Burton GJ, Kaufmann P, Huppertz B. Anatomy and genesis of the placenta. In:Neill JD, ed. Knobil and Neill's Physiology of Reproduction, Amsterdam:Academic Press, 2006:189-243
27.Martin BJ, Spicer SS. Ultrastructural features of cellular maturation and aging in human trophoblast. J UltrastructRes,1973,43:133-49
28.Burton GJ, Tham SW. The formation of vasculo-syncytial membranes in the human placenta. J Dev Physiol,1992,18:43-7.
29. Jones CJP, Fox H. Syncytial knots and intervillous bridges in the human placenta:an ultrastructural study. J Anat,1977,124:275-86.
30.Fox H. The significance of villous syncytial knots in the human placenta. J Obstet Gynaecol Br Commonw,1965,72:347-55
31. Alvarez H, Benedetti WL, Morel RL, et al. Trophoblast development gradient and its relationship to placental hemodynamics. Am J Obstet Gynecol,1970,106:416-20.
32.Burton GJ, Thurley KW, Skepper JN. A technique for correlative scanning and transmission electron microscopy of individual human placental villi:an example demonstrating syncytial sprouts in early gestation. Scanning Microsc,1991,5:451-8; discussion 58-9
33.Boyd JD, Hamilton WJ. The Human Placenta. Cambridge:W Heffer & Sons,1970:365
34. Simpson RA, Mayhew TM, Barnes PR. From 13 weeks to term, the trophoblast of human placenta grows by the continuous recruitment of new proliferative units:a studyof nuclear number using the disector. Placenta,1992,13:501-12
35.Huppertz B, Kingdom J, Caniggia I, et al. Hypoxia favours necrotic versus apoptotic shedding of placental syncytiotrophoblast into the maternal circulation. Placenta, 2003,24:181-90
36.Ellery PM, Cindrova-Davies T, Jauniaux E, et al. Evidence for transcriptional activity in the syncytiotrophoblast of the human placenta. Placenta,2009,30:329-34
37.Dimitrova DS. Nuclear transcription is essential for specification of mammalian replication origins. Genes Cells,2006,11:829-44
38.Heazell AE, Crocker IP. Live and let die—regulation of villous trophoblast apoptosis in normal and abnormal pregnancies.Placenta,2008,29:772-83
39.Cindrova-Davies T, Spasic-Boskovic O, Jauniaux E, et al. Nuclear factor-κB, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress:effects of antioxidant vitamins.Am J Pathol,2007,170: 1511-20
40.Cindrova-Davies T, Yung HW, Johns J, et al. Oxidative stress, gene expression, and protein changes induced in the human placenta during labor. Am J Pathol,2007,171: 1168-79
41.Toal M, Chan C, Fallah S, Alkazaleh F,et al.Usefulness of a placental profile in high-risk pregnancies. Am J Obstet Gynecol,2007,196:363.e1-7
42.Crocker I. Gabor Than Award Lecture 2006:pre-eclampsia and villous trophoblast turnover:perspectives and possibilities. Placenta,2007,28(Suppl A):S4-13
2. Pijnenborg R, Bland JM, Robertson WB, et al. The pattern of interstitial trophoblast invasion in early human pregnancy. Placenta,1981,2:303-316
3. Pijnenborg R. The placental bed. Hypertens Pregnancy,1996,15:7-23
4. Pijnenborg R, Bland JM, Robertson WB,et al. Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta,1983,4:397-414
5. Gerretsen G, Huisjes HJ, Elema JD. Morphological changes of spiral arteries in the placental bed in relation to pre-eclampsia and fetal growth retardation.Br J Obstet Gynaecol,1981,88:876-881
6. Pijnenborg R, Dixon G, Robertson WB,et al. The arterial migration of trophoblast in the uterus of the golden hamster. J Reprod Fertil,1974,40:269-280
7. Robson SC, Ball E, Lyall F,et al. Endovascular trophoblast invasion and spiral artery transformation:the "two wave" theory revisited. Placenta 2001,22:25
8. Brosens IA, Robertson WB and Dixon HG. The role of the spiral arteries in the pathogenesis of pre-eclampsia. Obstetrics and gynecology annual,1972,1:177-191
9. Pijnenborg R, Anthony J, Davey DA,et al. Placental bed spiral arteries in the hypertensive disorders of pregnancy. Br J Obstet Gynaecol,1991,98:648-655
10. Meekins JW, Pijnenborg R, Hanssens M, et al. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol,1994,101:669-674
11. Khong TY, De Wolf F, Robertson WB,et al. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol,1986,93:1049-1059
12. Lyall F, Simpson H, Robson SC, et al. Transforming growth factor β expression in human placenta and placental bed in normal pregnancy, preeclampsia and fetal growth restriction.Am J Pathol,2001,159:1827-1838
13. Lyall. Cell adhesion molecules:their role in pregnancy.Fetal Matern Med Rev,1998,10: 21-44
14. Huppert B, Kertschanska S, Demir A,et al. 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
15. Lala PK, Hamilton GS. Growth factors, proteases and protease inhibitors in the maternal-fetal dialogue.Placenta,1996,17:545-555
16. DiFederico E, Genbacev O,Fisher FJ.Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall.Am J Pathol,1999,155: 293-301
17. Kadyrov M,Schmitz C, Black S. Pre-eclampsia and maternal anaemia display reduced apoptosis and opposite invasive phenotypes of extravillous trophoblast. Placenta,2003, 24:540-548
18. Challier JC,Uzan S. The human placenta and its pathologies:focus on oxygen.Med Sci,2003,19:1111-1120
19. Rajakumar A, Conrad KP.Expression, ontogeny, and regulation of hypoxia-inducible transcription factors in the human placenta. Biol Reprod,2000,63:559-569
20. Moffett A,.NK cells and reproduction.Placenta,2004,25:K4
21. Lyall F. Development of the uteroplacental circulation:the role of carbon monoxide and nitric oxide in trophoblast invasion and spiral artery transformation. Microsc Res Tech,2003,60:402-411
22. C:\2010.3\ScienceDirect-Placenta Priming and remodelling of human placental bed spiral arteries during pregnancy-A Review.htm-bbib40Lyall F, Robson SC, Bulmer JN. Human trophoblast invasion and spiral artery transformation:the role of nitric oxide.Am J Pathol,1999,154:1105-1114
23. Lyall F, Barber A, Myatt L, et al. Hemeoxygenase expression in human placenta and placental bed implies a role in regulation of trophoblast invasion and placental function.FASEB J,2000,14:208-219
24. Maines MD. Heme oxygenase:function, multiplicity, regulatory mechanisms and clinical applications.FASEB J,1988,2:2257-2568
25. Maines MD.Carbon monoxide:an emerging regulator of cGMP in the brain.Mol Cell Neurosci,1993,4:389-397
1. Sibai BN, Caritis SN, Thom E, et al.Prevention of preeclampsia with low-dose aspirin in health nulliparous pregnant women. N Engl J Med,1993,329:1213-1218
2. Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med,1997,337:69-76
3. Walker JJ. Preeclampsia. Lancet,2000,356:1260-1265
4. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. Lancet,2001,357: 53-56
5. Goldenberg RL, Rouse DJ. Prevention of premature birth. N Engl J Med,1998,339: 313-320
6. Duley L. Maternal mortality associated with hypertensive disorders of pregnancy in Africa, Asia, Latin America and the Caribbean. Br J Obstet Gynaecol,1992,99: 547-553
7. Starzyk KA, Pijnenborg R, Salafia CM. Decidual and vascular pathophysiology in pregnancy compromise. Semin Reprod Endocrinol.1999,17(1):63-72
8. Lacroix MC, Guibourdenche J, Fournier T,et al. Stimulation of human trophoblast invasion by placental growth hormone. Endocrinology,146:2434-2444
9. Pollheimer J, Knofler M. Signalling pathways regulating the invasive differentiation of human trophoblasts, a review. Placenta,2005,26(Suppl A):S21-S30
10. Liotta LA. Tumour invasion and metastases, role of the basement membrane. Warner-Lambert Parke-Davis Award lecture. Am J Pathol,117:339-348
11. Bischof P. Endocrine, paracrine and autocrine regulation of trophoblastic metalloproteinases. Early Pregnancy,2001,5:30-31
12. Staff AC. An introduction to cell migration and invasion. Scand J Clin Lab Invest,2001, 61:257-268
13. Staff AC, Ranheim T, Henriksen T, et al.8-iso prostaglandin freduces trophblast invasion and matrix metalloproteinase activity. Hypertension,2000,35(6):1307-20
14. Berthold H, Kertschanska S. Immunohistochemistry of matrix metalloproteinase(MMP), their substrates and their inhibitors(TIMP) during trophoblast invasion in human placenta. Cell Tissue Res,1998,291:133-148
15. Naicker T, Khedun SM, Moodley J,et al. Quantitative analysis of trophoblast invasion in preeclampsia. Acta Obstet Gynecol Scand,2003,82:722-729
16. Sandra VA, Guy JW, Philip RD, et al. Uterine spiral artery remodeling involves endothelial apoptosis induced by extravillous trophoblasts through Fas/FasL interactions. Arteriosclerosis, Thrombosis, and Vascular Biology,2005,25:102-108
1. Pijnenborg R, Bland JM, Robertson WB, et al.The pattern of interstitial trophoblast invasion in early human pregnancy.Placenta,1981(2):303-316
2. Pijnenborg R, Bland JM, Robertson WB, et al. Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta,1983(4):397-414
3. Roberston WB, Khong TY, Brosens I, et al. The placental bed biopsy:review from three European centres. Am J Obstet Gynecol,1986(155):401-412
4. Pijnenborg R, Dixon G, Robertson WB et al.The arterial migration of trophoblast in the uterus of the golden hamster. J Reprod Fertil,1974(40):269-280
5. Robson SC, Ball E, Lyall F, et al. Endovascular trophoblast invasion and spiral artery transformation:the "two wave" theory revisited. Placenta,2001(22):A25
6. Christopher WR, Ian LS. Latest advances in understanding Preeclampsia. Science,2005, 308:1592-1594
7. Pijnenborg R, Dixon G, Robertson WB, et al. Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy. Placenta,1980,1:3-19
8. Enders AC, Blankenship TN. Modification of endometrial arteries during invasion by cytotrophoblast cells in the pregnant macaque. Acta Anat (Basel),1997,159:169-193
9. Ashton SV, Whitley GS, Dash PR, et al. Uterine spiral artery remodeling involves endothelial apoptosis induced by extravillous trophoblasts through Fas/FasL interactions. Arterioscler Thromb Vasc Biol,2005,25:102-108
10. Cartwright JE, Kenny LC, Dash PR, et al. Trophoblast invasion of spiral arteries:a novel in vitro model. Placenta,2002,23:232-235
11. Brosens IA, Robertson WB, Dixon HG The role of the spiral arteries in the pathogenesis of pre-eclampsia. Obstetrics and gynecology annual,1972(1):177-191
12. Fumio T, Rumiko N, Teruo A, et al. Proapoptotic effect of Proteolytic Activation of Matrix Metalloproteinases by streptococcus pyogenes Thiol Proteinase. Infect Immun,2004,72(8):4836-4847
1. Gordon MC. Maternal physiology. Normal and problem pregnancies,2007:55-84
2. Clapp JF, Capeless E. Cardiovascular function before, during, and after the first and subsequent pregnancies. Am J Cardiol,1997,80:1469-1473
3. Khong TY, De Wolf F, Robertson WB, et al. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol,1986,93:1049-1059
4. Khong TY, Liddell HS, Robertson WB. Defective haemochorial placentation as a cause of miscarriage. Br J Obstet Gynaecol,1987,94:649-655
5. Meekins JW, Pijnenborg R, Hanssens M, et al. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol.1994,101:669-674
6. Kim Y.M, Chaiworapongsa T, Gomez R, et al. Failure of the physiologic transformation of the spiral arteries in the placental bed in preterm premature rupture of membranes. Am J Obstet Gynecol,2002,187:1137-1142
7. Jauniaux E, Ramsay B, Campbell S. Ultrasonographic investigation of placental morphologic characteristics and size during the second trimester of pregnancy. Am J Obstet Gynecol,1994,170:130-137
8. Viero S, Chaddha V, Alkazaleh F, et al. Prognostic value of placental ultrasound in pregnancies complicated by absent end-diastolic flow velocity in the umbilical arteries. Placenta,2004,25:735-741
9. Toal M, Chan C, Fallah S, et al. Usefulness of a placental profile in high-risk pregnancies. Am J Obstet Gynecol,2007,196(363):el-e7
10. Crocker IP, Brownbill P, Hutchinson ES, et al. Irregular intervillous haemodynamics in the placental pathophysiology of pre-eclampsia. J Soc Gynecol Investig,2006,3(Suppl.): 232A
11. Burton GJ, Jones CJ. Syncytial knots, sprouts, apoptosis and trophoblast deportation from the human placenta. Taiwan J Obstet Gynecol,2009,48:28-37
12. Hung TH, Skepper JN, Charnock-Jones DS et al. Hypoxia/reoxygenation:a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circ Res,2002,90:1274-1281
13. Hung TH, Charnock-Jones DS, Skepper JN, et al. Secretion of tumour necrosis factor-a from human placental tissues induced by hypoxia-reoxygenation causes endothelial cell activation in vitro:a potential mediator of the inflammatory response in preeclampsia. Am J Pathol,2004,164:1049-1061
14. Soleymanlou N, Wu Y, Wang JX, et al. A novel Mtd splice isoform is responsible for trophoblast cell death in pre-eclampsia. Cell Death Differ,2005,12:441-452
15. Redman CW, Sacks GP, Sargent IL. Preeclampsia:an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol,1999,180:499-506
1. O'Brien SN, Welter BH,Price TM. Presence of leptin in breast cell lines and breast tumours. Biochem Biophys Res Commun,1999,259:695-698
2. Strickland S, Richards WG Invasion of the trophoblasts.Cell,1992,71:355-357
3. Genbacev O, Zhou Y, Ludlow JW, et al. Regulation of human placental development by oxygen tension. Science,1997,277:1669-1672
4. Redman CW. Cytotrophoblasts, masters of disguise.Nat Med,1997,3:610-611
5. Even-Ram S, Uziely B, Cohen P,et al. Thrombin receptor overexpression in malignant and physiological invasion processes.Nat Med,1998,4:909-914
6. Mullen CA. Review, analogies between trophoblastic and malignant cells. Am J Reprod Immunol,1998:39:41-49
7. Redman CW, Sargent IL and Starkey PM. The Human Placenta. Backwell Scientific Publications, Oxford,1993
8. Cross JC, Werb Z and Fisher. Implantation and the placenta, key pieces of the development puzzle. Science,1994,266:1508-1518
9. Loke YW and King A.Human Implantation. Cambridge University Press, Cambridge,1995
10. Lacroix MC, Guibourdenche J, Fournier T, et al. Stimulation of human trophoblast invasion by placental growth hormone. Endocrinology,2005,146:2434-2444
11. Pollheimer J,Knofler M. Signalling pathways regulating the invasive differentiation of human trophoblasts, a review. Placenta,2005,26(Suppl A):S21-S30
12. Poste QFidler IJ. The pathogenesis of cancer metastasis. Nature,1980,283;139-146
13.Bischof P,Campana A. A putative role for oncogenes in trophoblast invasion? Hum Reprod,2000,15(Suppl 6):51-58
14. Staff AC. An introduction to cell migration and invasion. Scand J Clin Lab Invest,2001, 61:257-268
15.Hahn WC,Weinberg RA.Modelling the molecular circuitry of cancer. Nat Rev Cancer,2002,2:331-341
16. Ullrich A, Coussens L, Hayflick JS, et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature,1984,309:418-425.
17. Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases, targets for cancer therapy. Nat Rev Cancer,2004,4:361-370
18. Hynes NE. ERBB receptors and cancer, the complexity of targeted inhibitors. Nat Rev Cancer,2005,5:341-354
19. Fulop V, Mok SC, Genest DR, et al. c-myc, c-erbB-2, c-fms and bcl-2 oncoproteins. Expression in normal placenta, partial and complete mole, and choriocarcinoma. J Reprod Med,1998,43:101-110
20. Doneda L, Bulfamante G, Grimoldi MG, et al. Localization of fos, jun, kit and SCF mRNA in human placenta throughout gestation using in situ RT-PCR. Early Pregnancy,1997,3:265-271
21.Hantschel O,Superti-Furga G. Regulation of the c-Ab1 and Bcr-Ab1 tyrosine kinases. Nat Rev Mol Cell Biol,2004,5:33-44
22. Takai N, Ueda T, Narahara H et al. Expression of c-Ets1 protein in normal human placenta. Gynecol Obstet Invest,2005,61:15-20
23. Bamberger AM, Bamberger CM, Aupers S,et al. Expression pattern of the activating protein-1 family of transcription factors in the human placenta. Mol Hum Reprod,2004,10:223-228
24. Montell DJ.Anchors away! Fos fosters anchor-cell invasion. Cell 2005,121:816-817
25. Sherwood DR, Butler JA, Kramer JM, et al. FOS-1 promotes basement-membrane removal during anchor-cell invasion in C. elegans. Cell,2005,121:951-962
26. Dang CV, O'Donnell KA, Juopperi T. The great MYC escape in tumourigenesis. Cancer Cell2005,8:177-178
27. Paumelle R, Tulasne D, Kherrouche Z, et al. Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. Oncogene,2002,21:2309-2319
28. Takai N, Ueda T, Narahara H et al. Expression of c-Etsl protein in normal human placenta. Gynecol Obstet Invest,2005,61:15-20
29. Downward J.Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer,2003,3:11-22
30. Malumbres M, Barbacid M. RAS oncogenes, the first 30 years. Nat Rev Cancer,2003, 3:459-465
31. Chakraborty C, Gleeson LM, McKinnon T et al. Regulation of human trophoblast migration and invasiveness. Can J Physiol Pharmacol,2002,80:116-124
32. Tseng JJ, Chou MM, Hsieh YT, et al.Differential expression of vascular endothelial growth factor, placenta growth factor and their receptors in placentae from pregnancies complicated by placenta accreta. Placenta,2006,27:70-78
33.Bischof P, Meisser A, Campana A. Paracrine and autocrine regulators of trophoblast invasion—a review. Placenta,2000,21(Suppl A)z;S55-S60
34. Bjorn SF, Hastrup N, Larsen JF, et al. Messenger RNA for membrane-type 2 matrix metalloproteinase, MT2-MMP, is expressed in human placenta of first trimester. Placenta,2000,21z:170-176
35. Isaka K, Usuda S, Ito H, et al. Expression and activity of matrix metalloproteinase 2 and 9 in human trophoblasts. Placenta,2003,24:53-64
36. Haimov-Kochman R, Friedmann Y, Prus D, et al. Localization of heparanase in normal and pathological human placenta. Mol Hum Reprod,2002,8:566-573
37. Chou CS, Beristain AG, MacCalman CD et al. Cellular localization of gonadotropin-releasing hormone (GnRH) I and GnRH II in first-trimester human placenta and decidua. J Clin Endocrinol Metab,2004,89:1459-1466
38.Ozturk M, Brown N, Milunsky A et al. Physiological studies of human chorionic gonadotropin and free subunits in the amniotic fluid compartment compared to those in maternal serum. J Clin Endocrinol Metab,1988,67:1117-1121
39. Marcillac I, Troalen F, Bidart JM, et al. Free human chorionic gonadotropin beta subunit in gonadal and nongonadal neoplasms. Cancer Res,1992,52:3901-3907
40. Malatesta M, Mannello F, Luchetti F, et al. Prostate-specific antigen synthesis and secretion by human placenta, a physiological kallikrein source during pregnancy. J Clin Endocrinol Metab,2000,85:317-321
41.Briese J, Oberndorfer M, Patschenik C, et al.Osteopontin is colocalized with the adhesion molecule CEACAM1 in the extravillous trophoblast of the human placenta and enhances invasion of CEACAM1-expressing placental cells. J Clin Endocrinol Metab,2005,90:5407-5413
42. Chen ME, Lin SH, Chung LW, et al. Isolation and characterization of PAGE-1 and GAGE-7. New genes expressed in the LNCaP prostate cancer progression model that share homology with melanoma-associated antigens. J Biol Chem,1998, 273:17618-17625
43. De Backer O, Arden KC, Boretti M, et al.Characterization of the GAGE genes that are expressed in various human cancers and in normal testis. Cancer Res,1999, 59:3157-3165
44. Kwon S, Kang SH, Ro J, et al. The melanoma antigen gene as a surveillance marker for the detection of circulating tumour cells in patients with breast carcinoma. Cancer,2005, 104:251-256
45. Lotem J, Netanely D, Domany E,et al. Human cancers overexpress genes that are specific to a variety of normal human tissues. Proc Natl Acad Sci USA,2005, 102:18556-18561
46. Lewis TS, Shapiro PS,Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res,1998,74:49-139
47. Pollheimer J, Knofler M. Signalling pathways regulating the invasive differentiation of human trophoblasts, a review. Placenta,2005,26(Suppl A):S21-S30
48. Kita N, Mitsushita J, Ohira S, et al. Expression and activation of MAP kinases, ERK1/2, in the human villous trophoblasts. Placenta,2003,24:164-172
49. Vivanco I,Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer,2002,2:489-501
50. Toker A, Yoeli-Lerner M. Akt signaling and cancer:surviving but not moving on. Cancer Res,2006,66:3963-3966
51. Vivanco I, Sawyers CL.The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer,2002,2:489-501
52. Cully M, You H, Levine AJ. Beyond PTEN mutations:the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer,2006,6:184-192
53.Fingar DC, Blenis J. Target of rapamycin (TOR):an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene,2004, 23:3151-3171
54. Duan C, Bauchat JR,Hsieh T. Phosphatidylinositol 3-kinase is required for insulin-like growth factor-I-induced vascular smooth muscle cell proliferation and migration. Circ Res,2000,86:15-23
55. Cartwright JE, Tse WK, Whitley GS. Hepatocyte growth factor induced human trophoblast motility involves phosphatidylinositol-3-kinase, mitogen-activated protein kinase, and inducible nitric oxide synthase. Exp Cell Res,2002,279:219-226
56. Qiu Q, Yang M, Tsang BK,et al. Both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signalling are required in epidermal growth factor-induced human trophoblast migration. Mol Hum Reprod,2004,10:677-684
57. Gabarra-Niecko V, Schaller MD,Dunty JM. FAK regulates biological processes important for the pathogenesis of cancer. Cancer Metastasis Rev,2003,22:359-374
58. Ilic D, Genbacev O, Jin F, Caceres E, et al.Plasma membrane-associated pY397FAK is a marker of cytotrophoblast invasion in vivo and in vitro. Am J Pathol,2001, 159:93-108
59. MacPhee DJ, Mostachfi H, Han R,et al. Focal adhesion kinase is a key mediator of human trophoblast development. Lab Invest,2001,81:1469-1483
60. Goode BL, Drubin DG, Barnes G. Functional cooperation between the microtubule and actin cytoskeletons. Curr Opin Cell Biol,2000,12:63-71
61. Shiokawa S, Iwashita M, Akimoto Y, et al. Small guanosine triphospatase RhoA and Rho-associated kinase as regulators of trophoblast migration. J Clin Endocrinol Metab,2002,87:5808-5816
62. Hanahan D,Weinberg RA.The hallmarks of cancer. Cell,2000,100:57-70
63. Birchmeier C, Birchmeier W, Gherardi E et al. Met, metastasis, motility and more. Nat Rev Mol Cell Biol,2003,4:915-925
64. Olsson AK, Dimberg A, Kreuger J et al. VEGF receptor signalling-in control of vascular function. Nat Rev Mol Cell Biol,2006,7:359-371
65. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia, role of the HIF system. Nat Med,2003,9:677-684
66. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell,2000,100:57-70
67. Khandwala HM, McCutcheon IE, Flyvbjerg A,et al. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev,2000,21:215-244
68. Chakraborty C, Gleeson LM, McKinnon T,et al.Regulation of human trophoblast migration and invasiveness. Can J Physiol Pharmacol,2000,80:116-124
69. Irish JM, Kotecha N, Nolan GP. Mapping normal and cancer cell signalling networks: towards single-cell proteomics. Nat Rev Cancer,2006,6:146-155
70. Guo W, Giancotti FG Integrin signalling during tumour progression. Nat Rev Mol Cell Biol,2004,5:816-826
71. Hood JD, Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer,2002,2:91-100
72. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3'kinase/AKT pathways. Oncogene,2005,24:7443-7454
73. Cohen M, Meisser A, Bischof P. Metalloproteinases and human placental invasiveness. Placenta,2006,27:783-793
74. Cully M, You H, Levine AJ et al. Beyond PTEN mutations:the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006,6:184-192
75. Bancroft CC, Chen Z, Yeh J, et al. Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-kappaB and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines. Int J Cancer,2002,99:538-548
76. Dempsey LA, Plummer TB, Coombes SL et al. Heparanase expression in invasive trophoblasts and acute vascular damage. Glycobiology,2000,10:467-475
77. Sinkovics JG, Horvath JC. Human natural killer cells, a comprehensive review. Int J Oncol,2005,27:5-47
78. Knofler M, Sooranna SR, Daoud G,et al. Trophoblast signalling, knowns and unknowns—a workshop report. Placenta,2005,26(Suppl A):S49-S51
1. Sibai BN, Caritis SN, Thom E, et al. Prevention of preeclampsia with low-dose aspirin in health. Nulliparous pregnant women. N Engl J Med,1993,329:1213-1218
2. Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med,1997,337:69-76
3. Walker JJ. Preeclampsia. Lancet,2000,356:1260-1265
4. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. Lancet,2001, 357:53-56
5. Von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy,2003,22:143-148
6. Huppertz B, Herrler A. Regulation of proliferation and apoptosis during development of the preimplantation embryo and the placenta. Birth Defects Res C Embryo Today, 2005,75:249-261
7. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia:current concepts. Am J Obstet Gynecol,1998,179:1359-1375
8. Kenny L, Baker PN. Maternal pathophysiology in pre-eclampsia. Baillieres Best Pract Res Clin Obstet Gynaecol,1999,13:59-75
9. Sekotory A, Ahmed M. Pre-eclampsia:hypotheses. J R Soc Health,2001,121:76-78
10.Wilson ML, Goodwin TM, Pan VL, et al. Molecular epidemiology of preeclampsia. Obstet Gynecol Surv,2003,58:39-66
11. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science, 2005,308:1592-1594
12.Knight M, Redman CW, Linton EA, et al. Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. Br J Obstet Gynaecol, 1998,105:632-640
13.Jauniaux E, Watson AL, Hempstock J, et al. 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
14.Huppertz B, Sammar M, Chefetz I, et al. Longitudinal determination of serum PP13 during development of preeclampsia. Fetal Diagn Therapy,2008,24(3):230-236
15.Huppertz B, Kingdom JC. Apoptosis in the trophoblast-role of apoptosis in placental morphogenesis. J Soc Gynecol Investig,2004,11:353-362
16.Huppertz B, Frank HG, Kingdom JC, et al. Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta. Histochem Cell Biol,1998,110: 495-508
17.Benirschke K, Kaufmann P, Baergen R. Pathology of the Human Placenta,5th ed., Springer New York,2006
18.Ikle FA. Trophoblastzellen im stromenden Blut. Schweiz Med Wochenschr,1964,91: 934-945
19.Goswami D, Tannetta DS, Magee LA, et al. Excess syncytiotrophoblast microparticle shedding is a feature of early-onset pre-eclampsia, but not normotensive intrauterine growth restriction. Placenta,2006,27:56-61
20.Freire-de-Lima CG, Xiao YQ, Gardai SJ, et al. Apoptotic cells, through transforming growth factor-beta, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. J Biol Chem, 2006,281:38376-38384
21.Krysko DV, D'Herde K, Vandenabeele P. Clearance of apoptotic and necrotic cells and its immunological consequences. Apoptosis,2006,11:1709-1726
22.Formigli L, Papucci L, Tani A, Schiavone N, et al. Aponecrosis:morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis. J Cell Physiol,2000,182:41-49
23. Gupta AK, Rusterholz C, Huppertz B, et al. A comparative study of the effect of three different syncytiotrophoblast microparticles preparations on endothelial cells. Placenta, 2005,26:59-66
24. Gaunt M, Ockleford CD. Microinjection of human placenta,Ⅱ:biologicalapplication. Placenta,1986,7:325-31
25.Burton GJ, Jauniaux E. Sonographic, stereological and Doppler flow velocimetric assessments of placental maturity.Br J Obstet Gynaecol,1995,102:818-25
26.Burton GJ, Kaufmann P, Huppertz B. Anatomy and genesis of the placenta. In:Neill JD, ed. Knobil and Neill's Physiology of Reproduction, Amsterdam:Academic Press, 2006:189-243
27.Martin BJ, Spicer SS. Ultrastructural features of cellular maturation and aging in human trophoblast. J UltrastructRes,1973,43:133-49
28.Burton GJ, Tham SW. The formation of vasculo-syncytial membranes in the human placenta. J Dev Physiol,1992,18:43-7.
29. Jones CJP, Fox H. Syncytial knots and intervillous bridges in the human placenta:an ultrastructural study. J Anat,1977,124:275-86.
30.Fox H. The significance of villous syncytial knots in the human placenta. J Obstet Gynaecol Br Commonw,1965,72:347-55
31. Alvarez H, Benedetti WL, Morel RL, et al. Trophoblast development gradient and its relationship to placental hemodynamics. Am J Obstet Gynecol,1970,106:416-20.
32.Burton GJ, Thurley KW, Skepper JN. A technique for correlative scanning and transmission electron microscopy of individual human placental villi:an example demonstrating syncytial sprouts in early gestation. Scanning Microsc,1991,5:451-8; discussion 58-9
33.Boyd JD, Hamilton WJ. The Human Placenta. Cambridge:W Heffer & Sons,1970:365
34. Simpson RA, Mayhew TM, Barnes PR. From 13 weeks to term, the trophoblast of human placenta grows by the continuous recruitment of new proliferative units:a studyof nuclear number using the disector. Placenta,1992,13:501-12
35.Huppertz B, Kingdom J, Caniggia I, et al. Hypoxia favours necrotic versus apoptotic shedding of placental syncytiotrophoblast into the maternal circulation. Placenta, 2003,24:181-90
36.Ellery PM, Cindrova-Davies T, Jauniaux E, et al. Evidence for transcriptional activity in the syncytiotrophoblast of the human placenta. Placenta,2009,30:329-34
37.Dimitrova DS. Nuclear transcription is essential for specification of mammalian replication origins. Genes Cells,2006,11:829-44
38.Heazell AE, Crocker IP. Live and let die—regulation of villous trophoblast apoptosis in normal and abnormal pregnancies.Placenta,2008,29:772-83
39.Cindrova-Davies T, Spasic-Boskovic O, Jauniaux E, et al. Nuclear factor-κB, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress:effects of antioxidant vitamins.Am J Pathol,2007,170: 1511-20
40.Cindrova-Davies T, Yung HW, Johns J, et al. Oxidative stress, gene expression, and protein changes induced in the human placenta during labor. Am J Pathol,2007,171: 1168-79
41.Toal M, Chan C, Fallah S, Alkazaleh F,et al.Usefulness of a placental profile in high-risk pregnancies. Am J Obstet Gynecol,2007,196:363.e1-7
42.Crocker I. Gabor Than Award Lecture 2006:pre-eclampsia and villous trophoblast turnover:perspectives and possibilities. Placenta,2007,28(Suppl A):S4-13