uNK细胞在人类早孕蜕膜血管生成中的作用
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摘要
目的：通过研究子宫自然杀伤细胞(uNK)、血管内皮生长因子(VEGF)、促血管生成素2(Ang2)在人类早孕子宫蜕膜中的表达及相关性分析，明确uNK细胞在人类早孕蜕膜血管生成中的作用机制。
方法：收集2005年9月-2005年10月在四川大学华西附二院妇产科拟行人工流产终止妊娠、年龄在19-39岁的45例早孕妇女的蜕膜组织，采用免疫组化的方法检测CD56、VEGF、F LK1、Ang2、Tie2和CD31在子宫蜕膜中的表达。同时采用CD56单克隆抗体快速染色子宫蜕膜冰冻组织切片，通过激光显微切割获得单个uNK细胞，进行巢式PCR的方法检测VEGF mRNA和Ang2 mRNA在单个uNK细胞中的表达。采用秩相关统计方法进行相关性分析。
结果：1、uNK细胞(CD56~+)大量存在于子宫蜕膜间质中，主要集中在血管和腺体周围的间质中，uNK细胞的胞膜或胞浆呈现阳性。uNK细胞在子宫蜕膜间质中的阳性率为23％(9％-46％)。
2、蜕膜组织中血管丰富，CD31特异性的表达于血管内皮细胞中，平均微血管密度(MVD)为5.5±2.3，与间质中uNK细胞的阳性表达率呈正相关(r=0.648，p＜0.01)。
3、VEGF蛋白在子宫蜕膜腺上皮细胞、血管内皮细胞以及间质细胞中皆有表达，蜕膜间质中VEGF表达阳性率为14％(3％-29％)。uNK细胞的阳性率与VEGF表达阳性率呈正相关(r=0.53，P＜0.01)。
Objective: To investigate the expression of CD56 bright natural killer cells, vascular endothelial growth factor(VEGF) and angiopoietin2 (Ang2) in decidua of human first-trimester, and to study the role of uterine natural killer cells (uNK) in decidual vascularizaton.
Method: Decidual tissue was collected from forty-five women with the first-trimester conception who wanted to stop their pregnancy from 2005 Sep to 2005 Oct in the Second University Hospital of Sichuan University. The immunohistochemistry technique was applied to ice-frozen decidual tissue samples using antibodies against CD56, VEGF, FLK1, Ang2, Tie2, and CD31. Fast immunohistochemistry technique was used to stain frozen section of decidua by anti-CD56 monoclonal antibody, then the single uNK cell that obtained through laser microdissection in the section, was detected mRNA expression of VEGF and Ang2 with nested polymerase chain reaction. The correlation among positive uNK cell, MVD, VEGF and Ang2 was measured by Spearman statistics method. Result: 1.There was a great amount of uNK cells scattered throughout the
方法：收集2005年9月-2005年10月在四川大学华西附二院妇产科拟行人工流产终止妊娠、年龄在19-39岁的45例早孕妇女的蜕膜组织，采用免疫组化的方法检测CD56、VEGF、F LK1、Ang2、Tie2和CD31在子宫蜕膜中的表达。同时采用CD56单克隆抗体快速染色子宫蜕膜冰冻组织切片，通过激光显微切割获得单个uNK细胞，进行巢式PCR的方法检测VEGF mRNA和Ang2 mRNA在单个uNK细胞中的表达。采用秩相关统计方法进行相关性分析。
结果：1、uNK细胞(CD56~+)大量存在于子宫蜕膜间质中，主要集中在血管和腺体周围的间质中，uNK细胞的胞膜或胞浆呈现阳性。uNK细胞在子宫蜕膜间质中的阳性率为23％(9％-46％)。
2、蜕膜组织中血管丰富，CD31特异性的表达于血管内皮细胞中，平均微血管密度(MVD)为5.5±2.3，与间质中uNK细胞的阳性表达率呈正相关(r=0.648，p＜0.01)。
3、VEGF蛋白在子宫蜕膜腺上皮细胞、血管内皮细胞以及间质细胞中皆有表达，蜕膜间质中VEGF表达阳性率为14％(3％-29％)。uNK细胞的阳性率与VEGF表达阳性率呈正相关(r=0.53，P＜0.01)。
Objective: To investigate the expression of CD56 bright natural killer cells, vascular endothelial growth factor(VEGF) and angiopoietin2 (Ang2) in decidua of human first-trimester, and to study the role of uterine natural killer cells (uNK) in decidual vascularizaton.
Method: Decidual tissue was collected from forty-five women with the first-trimester conception who wanted to stop their pregnancy from 2005 Sep to 2005 Oct in the Second University Hospital of Sichuan University. The immunohistochemistry technique was applied to ice-frozen decidual tissue samples using antibodies against CD56, VEGF, FLK1, Ang2, Tie2, and CD31. Fast immunohistochemistry technique was used to stain frozen section of decidua by anti-CD56 monoclonal antibody, then the single uNK cell that obtained through laser microdissection in the section, was detected mRNA expression of VEGF and Ang2 with nested polymerase chain reaction. The correlation among positive uNK cell, MVD, VEGF and Ang2 was measured by Spearman statistics method. Result: 1.There was a great amount of uNK cells scattered throughout the
引文
1. BA Croy, S Chantakru, S Esadeg, et al.Decidual natural killer cells: key regulators of placental development. J Reprod Immunol, 2002,57: 151-168.
2. BA Croy, Y Kiso. Granulated metrial gland cells: a natural killer cell subset of the pregnant murine uterus. Microscopy Research Technique 1993,25:189-200.
3. MJ Guimond, JA Luross, B Wang, et al. Absence of natural killer cells during murine pregnancy is associated with reproductive compromise in TgE26 mice. Biol Reprod, 1997, 56: 169-179.
4. JD Greenwood, K Minhas, JP Di Santo, et al. Ultrastructural studies of implantation sites from mice deficient in uterine natural killer cells. Placenta, 2000, 21: 693-702.
5 . AA Ashkar, JP Di Santo, BA Croy. Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturationduring normal murine pregnancy. J Exp Med, 2000, 192: 259-270.
6. P Celec, Y Yonemitsu. Vascular endothelial growth factor-basic science and its clinical implications. Pathophysiology, 2004, 11: 69-75.
7. C Wang, N Umesaki, H Nakamura, et al. Expression of vascular endothelial growth factor by granulated metrial gland cells in pregnant murine uteri. Cell Tiss Res, 2000, 300: 285-93.
8 . PC Maisonpierre, C Suri, PF Jones, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.Science,1997, 227: 55-60.
9. J Hirchenhain, I Huse, A Hess, et al. Differential expression of angiopoietins 1 and 2 and their receptor Tie-2 in human endometrium. Mol Hum Reprod, 2003, 9: 663-669.
10. XF Li, DS Charnock-Jones, E Zhang, et al. Angiogenic Growth Factor Messenger Ribonucleic Acids in Uterine Natural Killer Cells. J Clin Endocrinol Metab, 2001, 86: 1823-1834 .
11. A King, T Burrows, S Verma, et al. Human uterine lymphocytes. Hum Reprod Update, 1998, 4: 480-485.
12. JN Bulmerm, L Morrison, M Longfellow, et al. Granulated Lymphocytes in Human e n d o metrium:Histochemical and Immunohistochemical Studies.Hum Reprod, 1991,6:791-798
13. A Trundley, A Moffett. Human uterine leukocytes and pregnancy. Tissue Antigens, 2004, 63:1-12.
14. MJ Guimond, B Wang, BA Croy. Engraftment of Bone Marrow from Severe Combined immunodefient (SCID) Mice Reverses the Reproductive Deficits in Natural Killer Cell-deficient tg G Mice. J Exp Med, 1998,187: 217-223.
15. Z Marek, H Friederike, M Karsten, et al .Angiogenesis and vasculogenesis in pregnancy. Eur J Obste Gynecol Reprod Biol, 2003, 110: S10-S18.
16. WR Raymond. Role of Uterine Natural Killer Cells and Interferon in Placental Development. J Exp Med, 2000,192: fl-f4
17. S Shiraishi, K Nakagawa, N Kinukawa, et al. Immunohistochemical Localization of Vascular Endothelial Growth Factor In The Human Placenta.Placenta, 1996, 17: 111-121.
18. AM Sharkey, DS Charnock-Jones, CA Boocock, et al. Expression of mRNA for vascular endothelial growth factor in human placenta. J Reprod Fertil, 1993, 99: 609-615.
19. S Davis, TH Aldrich, PE Jones, et al. Isolation of angiopoietin-1, a ligand for the Tie-2 receptor, by secretion-trap expression cloning. Cell, 1996, 87: 1161-1169.
20. IB Lobov, PC Brooks, RA Lang, et al. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA, 2002, 99: 11205 - 11210.
1. MA Cooper, TA Fehniger, MA Caligiuri. The biology of human natural killer-cell subsets. Trend Immunol, 2001, 22 (11): 633-640.
2. A Trundley, A Moffett. Human uterine leukocytes and pregnancy. Tissue Antigens, 2004, 63:1-12.
3. BA Croy, Y Kiso. Granulated metrial gland cells: a natural killer cell subset of the pregnant murine uterus. Microsc Res Tech, 1993, 25: 189-200.
4. JN Bulmer, GE Lash. Human uterine natural killer cells: a reappraisal. Mol Immunol, 2005, 42: 511-521
5. LA Koopman, HD Kopcow, B Rybalov, et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med, 2003,198: 1201-12.
6. S Chantakru, C Miller, LE Roach, et al. Contributions from self-renewal and trafficking to the uterine NK cell population of early pregnancy. J Immunol, 2002,168: 22-8.
7. PA Linnemeyer, SB Pollack. Mab4H12 recognizes subsets of adherent-lymphokine activated killer cells and splenic NK cells from pregnant and neonatal mice. J Immunol. 1991, 146: 3729-3734.
8. AL Veenstra van Nieuwenhoven, MJ Heineman, MM Faas. The immunology of successful pregnancy. Hum Reprod Update, 2003, 9(4): 347-357.
9. U Kammerer, K Marzusch, S Krober, et al. A subset of CD56+ large granular lymphocytes in first-trimester human decidua are proliferating cells. Fertil Steril, 1999, 71: 74-79.
10. TA Henderson, PTK Saunders, A Moffett-King, et al. Steroid Receptor Expression in Uterine Natural Killer Cells. J Clin Endocrinol Metab, 2003, 88(1): 440-449.
11. A King, L Gardner, YW Loke. Evaluation of oestrogen and progesterone receptor expression in uterine mucosal lymphocytes. Hum. Reprod., 1996: 11:1079-82.
12. JR Head, CK Kresge, JD Young,et al. NKR-P+ cellsin the rat uterus: granulated metrial gland cells are of the natural killer cell lineage. Biol Reprod, 1994, 51:509-523.
13. W Ye, LM Zheng, JDE Yong, et al. he involvement of interleukin(il)-15 in regulating the differentiation of granulated metrial gland cells in mouse pregnancy uterus. J Exp Med, 1996,184: 2405-2410.
14. S Verma, SE. Hiby, YW Loke , et al. Human Decidual Natural Killer Cells Express the Receptor for and Respond to the Cytokine Interleukin 15. Biol Reprod., 2000, 62: 959-968 .
15. S Kim, K Iizuka, HL Aguila, et al. In vivo natural killer cell activities revealedby natural killer cell-deficient mice. Proc Natl Acad Sci, 2000, 97: 2731-2736.
16. A King, R Wheeler, NP Carter, et al. The response of human decidual leukocytes to IL-2. Cell Immunol 1992, 141: 409-421.
17. T Stallmach, T Ehrenstein, S Isenmann, et al. The role of perforin-expression by granular metrial gland cells in pregnancy. Eur J Immunol, 1995, 25: 3342-3348.
18. AA Ashkar, BA Croy. Functions of uterine natural killer cells are mediated by interferon gamma production during murine pregnancy. Semin Immun, 2001, 13: 235-241.
19. PP Jokhi, A King, AM Sharkey, et al. Screening for cytokine messenger ribonucleic acids in purified human decidual lymphocyte populations by the reverse-transcriptase polymerase chain reaction. J Immunol, 1994,153:4427-4435.
20. M Eriksson, SK Meadows, CR Wira, et al. Unique phenotype of human uterine NK cells and their regulation by endogenous TGF-β. J Leuko Biol, 2004, 76: 667-675.
21. A King. Uterine Leukocytes and Decidualisation. Hum Reprod Update, 2000, 6: 28-36.
22. M Zygmunt, F Herr, K Munstedt, et al. Angiogenesis and vasculogenesis in pregnancy. Eur J Obstet Gynecol Reprod Biol., 2003, 110: S10-S18.
23. P Carmeliet. Mechanisms of angiogenesis and arteriogenesis. Nat Med, 2000,6:389-395.
24. P Celec, Y Yonemitsu. Vascular endothelial growth factor-basic science and its clinical implications. Pathophysiology, 2004,11(2): 69-75.
25. XF Li, D S Charnock-Jones, E Zhang, et al. Angiogenic Growth Factor Messenger Ribonucleic Acids in Uterine Natural Killer Cells. J Clin Endocrinol Metab,2001,86 (4) : 1823-1834.
26. PC Maisonpierre, C Suri, PF Jones.Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science, 1997(227): 55-60.
27. S Davis, TH Aldrich. Isolation of angiopoietin-1, a ligand for the Tie-2 receptor, by secretion-trap expression cloning. Cell, 1996, 87(7): 1161-1169.
28. IB Lobov, PC Brooks, RA Lang, et al. Angiopoietin-2 displays VEGF- dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci, 2002, 99 (17):11205 -11210.
29. J Holash, PC Maisonpierre, D Compton, et al. Vessel cooption , regression and growth in tumors mediated by angiopoietins and EGF. Science, 1999, 284 (5422): 1994 -1998.
30. M Ashley, R Lesley, B Peter. Natural killer cells, miscarriage, and infertility.Br Med J, 2004, 329(7477): 1283-1285.
31. BA Croy. Hasn't the time come to replace the term metrial gland? J Reprod Immunol, 1999( 42): 127-129
32. MJ Guimond, BP Wang, BA Croy . Engraftment of Bone Marrow from Severe Combined Immunodeficient (SCID) Mice Reverses the Reproductive Deficits in Natural Killer Cell-deficient tg G Mice. J Exp Med, 1998,187(2): 217-223.
33. AA Ashkar, P James, D Santo, et al Interferon 7 Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy. J Exp Med, 2000,192(2): 259-270.
34. CM Craven, T Morgan, K Ward. Decidual spiral artery remodelling begins before cellular interaction with cytotrophoblasts. Placenta, 1998, 19:241-252.
35. WR Raymond. Role of Uterine Natural Killer Cells and Interferon Tin Placental Development. J Exp Med, 2000; 17, 192(2): fl-f4.
36. S Shiraishi, K Nakagawa, N Kinukawa, et al. Immunohistochemical localization of vascular endothelial growth factor in the human placenta.Placenta, 1996(17): 111-121.
37. CL Wang, N Umesaki, H Nakamura, et al. Expression of vascular endothelial growth factor by granulated metrial gland cells in pregnant murine uteri. Cell Tissue Res. 2000, 300: 285-293.
38. J Hirchenhain, I Huse, A Hess, et al. Differential expression of angiopoietins 1 and 2 and their receptor Tie-2 in human endometrium. Mol. Hum.Reprod, 2003, 9( 11): 663-669.
39. AA Ashkar, BA Croy. Interferon-gamma contributes to the normalcy of murine pregnancy. Biol Reprod, 1999, 61: 493-502
40. HL Chen, R Kamath, JL Pace, et al. Expression of the interferon-gamma receptor gene in mouse placentas is related to stage of gestation and is restricted to specific subpopulations of trophoblast cells. Placenta, 1994,15: 109-121.
2. BA Croy, Y Kiso. Granulated metrial gland cells: a natural killer cell subset of the pregnant murine uterus. Microscopy Research Technique 1993,25:189-200.
3. MJ Guimond, JA Luross, B Wang, et al. Absence of natural killer cells during murine pregnancy is associated with reproductive compromise in TgE26 mice. Biol Reprod, 1997, 56: 169-179.
4. JD Greenwood, K Minhas, JP Di Santo, et al. Ultrastructural studies of implantation sites from mice deficient in uterine natural killer cells. Placenta, 2000, 21: 693-702.
5 . AA Ashkar, JP Di Santo, BA Croy. Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturationduring normal murine pregnancy. J Exp Med, 2000, 192: 259-270.
6. P Celec, Y Yonemitsu. Vascular endothelial growth factor-basic science and its clinical implications. Pathophysiology, 2004, 11: 69-75.
7. C Wang, N Umesaki, H Nakamura, et al. Expression of vascular endothelial growth factor by granulated metrial gland cells in pregnant murine uteri. Cell Tiss Res, 2000, 300: 285-93.
8 . PC Maisonpierre, C Suri, PF Jones, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.Science,1997, 227: 55-60.
9. J Hirchenhain, I Huse, A Hess, et al. Differential expression of angiopoietins 1 and 2 and their receptor Tie-2 in human endometrium. Mol Hum Reprod, 2003, 9: 663-669.
10. XF Li, DS Charnock-Jones, E Zhang, et al. Angiogenic Growth Factor Messenger Ribonucleic Acids in Uterine Natural Killer Cells. J Clin Endocrinol Metab, 2001, 86: 1823-1834 .
11. A King, T Burrows, S Verma, et al. Human uterine lymphocytes. Hum Reprod Update, 1998, 4: 480-485.
12. JN Bulmerm, L Morrison, M Longfellow, et al. Granulated Lymphocytes in Human e n d o metrium:Histochemical and Immunohistochemical Studies.Hum Reprod, 1991,6:791-798
13. A Trundley, A Moffett. Human uterine leukocytes and pregnancy. Tissue Antigens, 2004, 63:1-12.
14. MJ Guimond, B Wang, BA Croy. Engraftment of Bone Marrow from Severe Combined immunodefient (SCID) Mice Reverses the Reproductive Deficits in Natural Killer Cell-deficient tg G Mice. J Exp Med, 1998,187: 217-223.
15. Z Marek, H Friederike, M Karsten, et al .Angiogenesis and vasculogenesis in pregnancy. Eur J Obste Gynecol Reprod Biol, 2003, 110: S10-S18.
16. WR Raymond. Role of Uterine Natural Killer Cells and Interferon in Placental Development. J Exp Med, 2000,192: fl-f4
17. S Shiraishi, K Nakagawa, N Kinukawa, et al. Immunohistochemical Localization of Vascular Endothelial Growth Factor In The Human Placenta.Placenta, 1996, 17: 111-121.
18. AM Sharkey, DS Charnock-Jones, CA Boocock, et al. Expression of mRNA for vascular endothelial growth factor in human placenta. J Reprod Fertil, 1993, 99: 609-615.
19. S Davis, TH Aldrich, PE Jones, et al. Isolation of angiopoietin-1, a ligand for the Tie-2 receptor, by secretion-trap expression cloning. Cell, 1996, 87: 1161-1169.
20. IB Lobov, PC Brooks, RA Lang, et al. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA, 2002, 99: 11205 - 11210.
1. MA Cooper, TA Fehniger, MA Caligiuri. The biology of human natural killer-cell subsets. Trend Immunol, 2001, 22 (11): 633-640.
2. A Trundley, A Moffett. Human uterine leukocytes and pregnancy. Tissue Antigens, 2004, 63:1-12.
3. BA Croy, Y Kiso. Granulated metrial gland cells: a natural killer cell subset of the pregnant murine uterus. Microsc Res Tech, 1993, 25: 189-200.
4. JN Bulmer, GE Lash. Human uterine natural killer cells: a reappraisal. Mol Immunol, 2005, 42: 511-521
5. LA Koopman, HD Kopcow, B Rybalov, et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med, 2003,198: 1201-12.
6. S Chantakru, C Miller, LE Roach, et al. Contributions from self-renewal and trafficking to the uterine NK cell population of early pregnancy. J Immunol, 2002,168: 22-8.
7. PA Linnemeyer, SB Pollack. Mab4H12 recognizes subsets of adherent-lymphokine activated killer cells and splenic NK cells from pregnant and neonatal mice. J Immunol. 1991, 146: 3729-3734.
8. AL Veenstra van Nieuwenhoven, MJ Heineman, MM Faas. The immunology of successful pregnancy. Hum Reprod Update, 2003, 9(4): 347-357.
9. U Kammerer, K Marzusch, S Krober, et al. A subset of CD56+ large granular lymphocytes in first-trimester human decidua are proliferating cells. Fertil Steril, 1999, 71: 74-79.
10. TA Henderson, PTK Saunders, A Moffett-King, et al. Steroid Receptor Expression in Uterine Natural Killer Cells. J Clin Endocrinol Metab, 2003, 88(1): 440-449.
11. A King, L Gardner, YW Loke. Evaluation of oestrogen and progesterone receptor expression in uterine mucosal lymphocytes. Hum. Reprod., 1996: 11:1079-82.
12. JR Head, CK Kresge, JD Young,et al. NKR-P+ cellsin the rat uterus: granulated metrial gland cells are of the natural killer cell lineage. Biol Reprod, 1994, 51:509-523.
13. W Ye, LM Zheng, JDE Yong, et al. he involvement of interleukin(il)-15 in regulating the differentiation of granulated metrial gland cells in mouse pregnancy uterus. J Exp Med, 1996,184: 2405-2410.
14. S Verma, SE. Hiby, YW Loke , et al. Human Decidual Natural Killer Cells Express the Receptor for and Respond to the Cytokine Interleukin 15. Biol Reprod., 2000, 62: 959-968 .
15. S Kim, K Iizuka, HL Aguila, et al. In vivo natural killer cell activities revealedby natural killer cell-deficient mice. Proc Natl Acad Sci, 2000, 97: 2731-2736.
16. A King, R Wheeler, NP Carter, et al. The response of human decidual leukocytes to IL-2. Cell Immunol 1992, 141: 409-421.
17. T Stallmach, T Ehrenstein, S Isenmann, et al. The role of perforin-expression by granular metrial gland cells in pregnancy. Eur J Immunol, 1995, 25: 3342-3348.
18. AA Ashkar, BA Croy. Functions of uterine natural killer cells are mediated by interferon gamma production during murine pregnancy. Semin Immun, 2001, 13: 235-241.
19. PP Jokhi, A King, AM Sharkey, et al. Screening for cytokine messenger ribonucleic acids in purified human decidual lymphocyte populations by the reverse-transcriptase polymerase chain reaction. J Immunol, 1994,153:4427-4435.
20. M Eriksson, SK Meadows, CR Wira, et al. Unique phenotype of human uterine NK cells and their regulation by endogenous TGF-β. J Leuko Biol, 2004, 76: 667-675.
21. A King. Uterine Leukocytes and Decidualisation. Hum Reprod Update, 2000, 6: 28-36.
22. M Zygmunt, F Herr, K Munstedt, et al. Angiogenesis and vasculogenesis in pregnancy. Eur J Obstet Gynecol Reprod Biol., 2003, 110: S10-S18.
23. P Carmeliet. Mechanisms of angiogenesis and arteriogenesis. Nat Med, 2000,6:389-395.
24. P Celec, Y Yonemitsu. Vascular endothelial growth factor-basic science and its clinical implications. Pathophysiology, 2004,11(2): 69-75.
25. XF Li, D S Charnock-Jones, E Zhang, et al. Angiogenic Growth Factor Messenger Ribonucleic Acids in Uterine Natural Killer Cells. J Clin Endocrinol Metab,2001,86 (4) : 1823-1834.
26. PC Maisonpierre, C Suri, PF Jones.Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science, 1997(227): 55-60.
27. S Davis, TH Aldrich. Isolation of angiopoietin-1, a ligand for the Tie-2 receptor, by secretion-trap expression cloning. Cell, 1996, 87(7): 1161-1169.
28. IB Lobov, PC Brooks, RA Lang, et al. Angiopoietin-2 displays VEGF- dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci, 2002, 99 (17):11205 -11210.
29. J Holash, PC Maisonpierre, D Compton, et al. Vessel cooption , regression and growth in tumors mediated by angiopoietins and EGF. Science, 1999, 284 (5422): 1994 -1998.
30. M Ashley, R Lesley, B Peter. Natural killer cells, miscarriage, and infertility.Br Med J, 2004, 329(7477): 1283-1285.
31. BA Croy. Hasn't the time come to replace the term metrial gland? J Reprod Immunol, 1999( 42): 127-129
32. MJ Guimond, BP Wang, BA Croy . Engraftment of Bone Marrow from Severe Combined Immunodeficient (SCID) Mice Reverses the Reproductive Deficits in Natural Killer Cell-deficient tg G Mice. J Exp Med, 1998,187(2): 217-223.
33. AA Ashkar, P James, D Santo, et al Interferon 7 Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy. J Exp Med, 2000,192(2): 259-270.
34. CM Craven, T Morgan, K Ward. Decidual spiral artery remodelling begins before cellular interaction with cytotrophoblasts. Placenta, 1998, 19:241-252.
35. WR Raymond. Role of Uterine Natural Killer Cells and Interferon Tin Placental Development. J Exp Med, 2000; 17, 192(2): fl-f4.
36. S Shiraishi, K Nakagawa, N Kinukawa, et al. Immunohistochemical localization of vascular endothelial growth factor in the human placenta.Placenta, 1996(17): 111-121.
37. CL Wang, N Umesaki, H Nakamura, et al. Expression of vascular endothelial growth factor by granulated metrial gland cells in pregnant murine uteri. Cell Tissue Res. 2000, 300: 285-293.
38. J Hirchenhain, I Huse, A Hess, et al. Differential expression of angiopoietins 1 and 2 and their receptor Tie-2 in human endometrium. Mol. Hum.Reprod, 2003, 9( 11): 663-669.
39. AA Ashkar, BA Croy. Interferon-gamma contributes to the normalcy of murine pregnancy. Biol Reprod, 1999, 61: 493-502
40. HL Chen, R Kamath, JL Pace, et al. Expression of the interferon-gamma receptor gene in mouse placentas is related to stage of gestation and is restricted to specific subpopulations of trophoblast cells. Placenta, 1994,15: 109-121.