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Regulation of Angiogenesis in the Human Endometrium

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Uterine Endometrial Function

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Abstract

The physiological changes in the endometrium in response to hypoxia and female sex hormones are associated with profound angiogenesis. Hypoxia in the endometrial tissues is a major regulator of endometrial angiogenesis and remodeling during menstruation. Estradiol plays an important role in the reconstruction of a new vascular network and rapid vessel growth in the endometrium. Progesterone is a key factor in vascular maturation and decidualization. Further, endometrial angiogenesis is tightly controlled by a variety of angiogenic and antiangiogenic factors including vascular endothelial growth factor (VEGF), soluble VEGF receptor-1, angiopoietin, and CXCL12. Hypoxia and female sex hormones are involved in the regulation of the angiogenic factors in an independent manner in human endometrium. Analysis of the process of angiogenesis in the human endometrium will enhance our understanding of normal endometrial vascular remodeling.

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References

  1. Okada H, Tsuzuki T, Shindoh H, Nishigaki A, Yasuda K, Kanzaki H. Regulation of decidualization and angiogenesis in the human endometrium: mini review. J Obstet Gynaecol Res. 2014;40:1180–7.

    Article  CAS  PubMed  Google Scholar 

  2. Lessey BA, Young SL. Homeostasis imbalance in the endometrium of women with implantation defects: the role of estrogen and progesterone. Semin Reprod Med. 2014;32:365–75.

    Article  CAS  PubMed  Google Scholar 

  3. Henriet P, Gaide Chevronnay HP, Marbaix E. The endocrine and paracrine control of menstruation. Mol Cell Endocrinol. 2012;358:197–207.

    Article  CAS  PubMed  Google Scholar 

  4. Plaisier M. Decidualisation and angiogenesis. Best Pract Res Clin Obstet Gynaecol. 2011;25:259–71.

    Article  PubMed  Google Scholar 

  5. Albrecht ED, Pepe GJ. Steroid hormone regulation of angiogenesis in the primate endometrium. Front Biosci. 2003;8:d416–29.

    Article  CAS  PubMed  Google Scholar 

  6. Petracco RG, Kong A, Grechukhina O, Krikun G, Taylor HS. Global gene expression profiling of proliferative phase endometrium reveals distinct functional subdivisions. Reprod Sci. 2012;19:1138–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003;9:653–60.

    Article  CAS  PubMed  Google Scholar 

  8. Girling JE, Rogers PA. Recent advances in endometrial angiogenesis research. Angiogenesis. 2005;8:89–99.

    Article  PubMed  Google Scholar 

  9. Smith SK. Angiogenesis and implantation. Hum Reprod. 2000;15 Suppl 6:59–66.

    PubMed  Google Scholar 

  10. Hey-Cunningham AJ, Peters KM, Zevallos HB, Berbic M, Markham R, Fraser IS. Angiogenesis, lymphangiogenesis and neurogenesis in endometriosis. Front Biosci (Elite Ed). 2013;5:1033–56.

    Article  Google Scholar 

  11. Pittatore G, Moggio A, Benedetto C, Bussolati B, Revelli A. Endometrial adult/progenitor stem cells: pathogenetic theory and new antiangiogenic approach for endometriosis therapy. Reprod Sci. 2014;21:296–304.

    Article  CAS  PubMed  Google Scholar 

  12. Bradford LS, Rauh-Hain JA, Schorge J, Birrer MJ, Dizon DS. Advances in the management of recurrent endometrial cancer. Am J Clin Oncol. 2015;38:206–12.

    Article  CAS  PubMed  Google Scholar 

  13. Virdis A, Dell’Agnello U, Taddei S. Impact of inflammation on vascular disease in hypertension. Maturitas. 2014;78:179–83.

    Article  CAS  PubMed  Google Scholar 

  14. Schulte-Merker S, Sabine A, Petrova TV. Lymphatic vascular morphogenesis in development, physiology, and disease. J Cell Biol. 2011;193:607–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jabbour HN, Kelly RW, Fraser HM, Critchley HO. Endocrine regulation of menstruation. Endocr Rev. 2006;27:17–46.

    Article  CAS  PubMed  Google Scholar 

  16. Aberdeen GW, Wiegand SJ, Bonagura Jr TW, Pepe GJ, Albrecht ED. Vascular endothelial growth factor mediates the estrogen-induced breakdown of tight junctions between and increase in proliferation of microvessel endothelial cells in the baboon endometrium. Endocrinology. 2008;149:6076–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Salamonsen LA. Tissue injury and repair in the female human reproductive tract. Reproduction. 2003;125:301–11.

    Article  CAS  PubMed  Google Scholar 

  18. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40:294–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Semenza GL. Oxygen sensing, homeostasis, and disease. N Engl J Med. 2011;365:537–47.

    Article  CAS  PubMed  Google Scholar 

  20. Szablowska-Gadomska I, Zayat V, Buzanska L. Influence of low oxygen tensions on expression of pluripotency genes in stem cells. Acta Neurobiol Exp (Wars). 2011;71:86–93.

    Google Scholar 

  21. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin Jr WG. Hifalpha targeted for vhl-mediated destruction by proline hydroxylation: implications for o2 sensing. Science. 2001;292:464–8.

    Article  CAS  PubMed  Google Scholar 

  22. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of hif-alpha to the von hippel-lindau ubiquitylation complex by o2-regulated prolyl hydroxylation. Science. 2001;292:468–72.

    Article  CAS  PubMed  Google Scholar 

  23. Tsuzuki T, Okada H, Cho H, Tsuji S, Nishigaki A, Yasuda K, Kanzaki H. Hypoxic stress simultaneously stimulates vascular endothelial growth factor via hypoxia-inducible factor-1alpha and inhibits stromal cell-derived factor-1 in human endometrial stromal cells. Hum Reprod. 2012;27:523–30.

    Article  CAS  PubMed  Google Scholar 

  24. Ardyanto TD, Osaki M, Tokuyasu N, Nagahama Y, Ito H. Cocl2-induced hif-1alpha expression correlates with proliferation and apoptosis in mkn-1 cells: a possible role for the pi3k/akt pathway. Int J Oncol. 2006;29:549–55.

    CAS  PubMed  Google Scholar 

  25. Critchley HO, Osei J, Henderson TA, Boswell L, Sales KJ, Jabbour HN, Hirani N. Hypoxia-inducible factor-1alpha expression in human endometrium and its regulation by prostaglandin e-series prostanoid receptor 2 (ep2). Endocrinology. 2006;147:744–53.

    Article  CAS  PubMed  Google Scholar 

  26. Lobo SC, Huang ST, Germeyer A, Dosiou C, Vo KC, Tulac S, Nayak NR, Giudice LC. The immune environment in human endometrium during the window of implantation. Am J Reprod Immunol. 2004;52:244–51.

    Article  PubMed  Google Scholar 

  27. Okada H, Nie G, Salamonsen LA. Requirement for proprotein convertase 5/6 during decidualization of human endometrial stromal cells in vitro. J Clin Endocrinol Metab. 2005;90:1028–34.

    Article  CAS  PubMed  Google Scholar 

  28. Dimitriadis E, Nie G, Hannan NJ, Paiva P, Salamonsen LA. Local regulation of implantation at the human fetal-maternal interface. Int J Dev Biol. 2010;54:313–22.

    Article  CAS  PubMed  Google Scholar 

  29. Singh M, Chaudhry P, Asselin E. Bridging endometrial receptivity and implantation: network of hormones, cytokines, and growth factors. J Endocrinol. 2011;210:5–14.

    Article  CAS  PubMed  Google Scholar 

  30. Hamilton KJ, Arao Y, Korach KS. Estrogen hormone physiology: reproductive findings from estrogen receptor mutant mice. Reprod Biol. 2014;14:3–8.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Koos RD. Minireview: putting physiology back into estrogens’ mechanism of action. Endocrinology. 2011;152:4481–8.

    Article  CAS  PubMed  Google Scholar 

  32. Hara Y, Waters EM, McEwen BS, Morrison JH. Estrogen effects on cognitive and synaptic health over the lifecourse. Physiol Rev. 2015;95:785–807.

    Article  CAS  PubMed  Google Scholar 

  33. Maruyama T, Yoshimura Y. Molecular and cellular mechanisms for differentiation and regeneration of the uterine endometrium. Endocr J. 2008;55:795–810.

    Article  CAS  PubMed  Google Scholar 

  34. Conneely OM, Mulac-Jericevic B, DeMayo F, Lydon JP, O’Malley BW. Reproductive functions of progesterone receptors. Recent Prog Horm Res. 2002;57:339–55.

    Article  CAS  PubMed  Google Scholar 

  35. Wetendorf M, DeMayo FJ. The progesterone receptor regulates implantation, decidualization, and glandular development via a complex paracrine signaling network. Mol Cell Endocrinol. 2012;357:108–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee SK, Kim CJ, Kim DJ, Kang JH. Immune cells in the female reproductive tract. Immune Netw. 2015;15:16–26.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Wang H, Dey SK. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet. 2006;7:185–99.

    Article  PubMed  CAS  Google Scholar 

  38. Croy BA, Chen Z, Hofmann AP, Lord EM, Sedlacek AL, Gerber SA. Imaging of vascular development in early mouse decidua and its association with leukocytes and trophoblasts. Biol Reprod. 2012;87:125.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Hofmann AP, Gerber SA, Croy BA. Uterine natural killer cells pace early development of mouse decidua basalis. Mol Hum Reprod. 2014;20:66–76.

    Article  CAS  PubMed  Google Scholar 

  40. Lima PD, Zhang J, Dunk C, Lye SJ, Croy BA. Leukocyte driven-decidual angiogenesis in early pregnancy. Cell Mol Immunol. 2014;11:522–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wallace AE, Fraser R, Gurung S, Goulwara SS, Whitley GS, Johnstone AP, Cartwright JE. Increased angiogenic factor secretion by decidual natural killer cells from pregnancies with high uterine artery resistance alters trophoblast function. Hum Reprod. 2014;29:652–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S, Prus D, Cohen-Daniel L, Arnon TI, Manaster I, Gazit R, Yutkin V, Benharroch D, Porgador A, Keshet E, Yagel S, Mandelboim O. Decidual nk cells regulate key developmental processes at the human fetal-maternal interface. Nat Med. 2006;12:1065–74.

    Article  CAS  PubMed  Google Scholar 

  43. Wallace AE, Fraser R, Cartwright JE. Extravillous trophoblast and decidual natural killer cells: a remodelling partnership. Hum Reprod Update. 2012;18:458–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Henderson TA, Saunders PT, Moffett-King A, Groome NP, Critchley HO. Steroid receptor expression in uterine natural killer cells. J Clin Endocrinol Metab. 2003;88:440–9.

    Article  CAS  PubMed  Google Scholar 

  45. Kitaya K, Yamaguchi T, Honjo H. Central role of interleukin-15 in postovulatory recruitment of peripheral blood cd16(-) natural killer cells into human endometrium. J Clin Endocrinol Metab. 2005;90:2932–40.

    Article  CAS  PubMed  Google Scholar 

  46. Verbist KC, Klonowski KD. Functions of il-15 in anti-viral immunity: multiplicity and variety. Cytokine. 2012;59:467–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Santoni A, Carlino C, Gismondi A. Uterine nk cell development, migration and function. Reprod Biomed Online. 2008;16:202–10.

    Article  CAS  PubMed  Google Scholar 

  48. Okada H, Nakajima T, Sanezumi M, Ikuta A, Yasuda K, Kanzaki H. Progesterone enhances interleukin-15 production in human endometrial stromal cells in vitro. J Clin Endocrinol Metab. 2000;85:4765–70.

    CAS  PubMed  Google Scholar 

  49. Okada S, Okada H, Sanezumi M, Nakajima T, Yasuda K, Kanzaki H. Expression of interleukin-15 in human endometrium and decidua. Mol Hum Reprod. 2000;6:75–80.

    Article  CAS  PubMed  Google Scholar 

  50. Okada H, Nakajima T, Yasuda K, Kanzaki H. Interleukin-1 inhibits interleukin-15 production by progesterone during in vitro decidualization in human. J Reprod Immunol. 2004;61:3–12.

    Article  CAS  PubMed  Google Scholar 

  51. Ramathal CY, Bagchi IC, Taylor RN, Bagchi MK. Endometrial decidualization: of mice and men. Semin Reprod Med. 2010;28:17–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Cho H, Okada H, Tsuzuki T, Nishigaki A, Yasuda K, Kanzaki H. Progestin-induced heart and neural crest derivatives expressed transcript 2 is associated with fibulin-1 expression in human endometrial stromal cells. Fertil Steril. 2013;99:248–55.

    Article  CAS  PubMed  Google Scholar 

  53. Okada H, Nakajima T, Yoshimura T, Yasuda K, Kanzaki H. The inhibitory effect of dienogest, a synthetic steroid, on the growth of human endometrial stromal cells in vitro. Mol Hum Reprod. 2001;7:341–7.

    Article  CAS  PubMed  Google Scholar 

  54. Shindoh H, Okada H, Tsuzuki T, Nishigaki A, Kanzaki H. Requirement of heart and neural crest derivatives-expressed transcript 2 during decidualization of human endometrial stromal cells in vitro. Fertil Steril. 2014;2014(101):1781–90. e1781–1785.

    Article  CAS  Google Scholar 

  55. Okada H, Sanezumi M, Nakajima T, Okada S, Yasuda K, Kanzaki H. Rapid down-regulation of cd63 transcription by progesterone in human endometrial stromal cells. Mol Hum Reprod. 1999;5:554–8.

    Article  CAS  PubMed  Google Scholar 

  56. Okada H, Nakajima T, Yoshimura T, Yasuda K, Kanzaki H. Microarray analysis of genes controlled by progesterone in human endometrial stromal cells in vitro. Gynecol Endocrinol. 2003;17:271–80.

    Article  CAS  PubMed  Google Scholar 

  57. Binder NK, Evans J, Gardner DK, Salamonsen LA, Hannan NJ. Endometrial signals improve embryo outcome: functional role of vascular endothelial growth factor isoforms on embryo development and implantation in mice. Hum Reprod. 2014;29:2278–86.

    Article  CAS  PubMed  Google Scholar 

  58. Chakraborty I, Das SK, Dey SK. Differential expression of vascular endothelial growth factor and its receptor mrnas in the mouse uterus around the time of implantation. J Endocrinol. 1995;147:339–52.

    Article  CAS  PubMed  Google Scholar 

  59. Charnock-Jones DS, Sharkey AM, Rajput-Williams J, Burch D, Schofield JP, Fountain SA, Boocock CA, Smith SK. Identification and localization of alternately spliced mrnas for vascular endothelial growth factor in human uterus and estrogen regulation in endometrial carcinoma cell lines. Biol Reprod. 1993;48:1120–8.

    Article  CAS  PubMed  Google Scholar 

  60. Weston G, Rogers PA. Endometrial angiogenesis. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000;14:919–36.

    Article  CAS  PubMed  Google Scholar 

  61. Gargett CE, Rogers PA. Human endometrial angiogenesis. Reproduction. 2001;121:181–6.

    Article  CAS  PubMed  Google Scholar 

  62. Smith SK. Regulation of angiogenesis in the endometrium. Trends Endocrinol Metab. 2001;12:147–51.

    Article  CAS  PubMed  Google Scholar 

  63. Shibuya M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol. 2006;39:469–78.

    Article  CAS  PubMed  Google Scholar 

  64. Nishigaki A, Okada H, Okamoto R, Shimoi K, Miyashiro H, Yasuda K, Kanzaki H. The concentration of human follicular fluid stromal cell-derived factor-1 is correlated with luteinization in follicles. Gynecol Endocrinol. 2013;29:230–4.

    Article  CAS  PubMed  Google Scholar 

  65. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25:581–611.

    Article  CAS  PubMed  Google Scholar 

  66. Shifren JL, Tseng JF, Zaloudek CJ, Ryan IP, Meng YG, Ferrara N, Jaffe RB, Taylor RN. Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis. J Clin Endocrinol Metab. 1996;81:3112–8.

    CAS  PubMed  Google Scholar 

  67. Das SK, Chakraborty I, Wang J, Dey SK, Hoffman LH. Expression of vascular endothelial growth factor (vegf) and vegf-receptor messenger ribonucleic acids in the peri-implantation rabbit uterus. Biol Reprod. 1997;56:1390–9.

    Article  CAS  PubMed  Google Scholar 

  68. Evans PW, Wheeler T, Anthony FW, Osmond C. A longitudinal study of maternal serum vascular endothelial growth factor in early pregnancy. Hum Reprod. 1998;13:1057–62.

    Article  CAS  PubMed  Google Scholar 

  69. Shibuya M. Vegf-vegfr signals in health and disease. Biomol Ther (Seoul). 2014;22:1–9.

    Article  CAS  Google Scholar 

  70. Wittko-Schneider IM, Schneider FT, Plate KH. Brain homeostasis: vegf receptor 1 and 2-two unequal brothers in mind. Cell Mol Life Sci. 2013;70:1705–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lockwood CJ. Mechanisms of normal and abnormal endometrial bleeding. Menopause. 2011;18:408–11.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Becker CM, D’Amato RJ. Angiogenesis and antiangiogenic therapy in endometriosis. Microvasc Res. 2007;74:121–30.

    Article  CAS  PubMed  Google Scholar 

  73. Fan X, Krieg S, Kuo CJ, Wiegand SJ, Rabinovitch M, Druzin ML, Brenner RM, Giudice LC, Nayak NR. Vegf blockade inhibits angiogenesis and reepithelialization of endometrium. FASEB J. 2008;22:3571–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Sharkey AM, Day K, McPherson A, Malik S, Licence D, Smith SK, Charnock-Jones DS. Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia. J Clin Endocrinol Metab. 2000;85:402–9.

    CAS  PubMed  Google Scholar 

  75. Yoshie M, Miyajima E, Kyo S, Tamura K. Stathmin, a microtubule regulatory protein, is associated with hypoxia-inducible factor-1alpha levels in human endometrial and endothelial cells. Endocrinology. 2009;150:2413–8.

    Article  CAS  PubMed  Google Scholar 

  76. Breen E, Tang K, Olfert M, Knapp A, Wagner P. Skeletal muscle capillarity during hypoxia: vegf and its activation. High Alt Med Biol. 2008;9:158–66.

    Article  CAS  PubMed  Google Scholar 

  77. Kimura H, Weisz A, Kurashima Y, Hashimoto K, Ogura T, D’Acquisto F, Addeo R, Makuuchi M, Esumi H. Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. Blood. 2000;95:189–97.

    CAS  PubMed  Google Scholar 

  78. Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res. 2005;65:9047–55.

    Article  CAS  PubMed  Google Scholar 

  79. Niklaus AL, Aberdeen GW, Babischkin JS, Pepe GJ, Albrecht ED. Effect of estrogen on vascular endothelial growth/permeability factor expression by glandular epithelial and stromal cells in the baboon endometrium. Biol Reprod. 2003;68:1997–2004.

    Article  CAS  PubMed  Google Scholar 

  80. Nayak NR, Brenner RM. Vascular proliferation and vascular endothelial growth factor expression in the rhesus macaque endometrium. J Clin Endocrinol Metab. 2002;87:1845–55.

    Article  CAS  PubMed  Google Scholar 

  81. Herve MA, Meduri G, Petit FG, Domet TS, Lazennec G, Mourah S, Perrot-Applanat M. Regulation of the vascular endothelial growth factor (vegf) receptor flk-1/kdr by estradiol through vegf in uterus. J Endocrinol. 2006;188:91–9.

    Article  CAS  PubMed  Google Scholar 

  82. Okada H, Tsutsumi A, Imai M, Nakajima T, Yasuda K, Kanzaki H. Estrogen and selective estrogen receptor modulators regulate vascular endothelial growth factor and soluble vascular endothelial growth factor receptor 1 in human endometrial stromal cells. Fertil Steril. 2010;93:2680–6.

    Article  CAS  PubMed  Google Scholar 

  83. Elkin M, Orgel A, Kleinman HK. An angiogenic switch in breast cancer involves estrogen and soluble vascular endothelial growth factor receptor 1. J Natl Cancer Inst. 2004;96:875–8.

    Article  CAS  PubMed  Google Scholar 

  84. Garvin S, Nilsson UW, Dabrosin C. Effects of oestradiol and tamoxifen on vegf, soluble vegfr-1, and vegfr-2 in breast cancer and endothelial cells. Br J Cancer. 2005;93:1005–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sharkey AM, Catalano R, Evans A, Charnock-Jones DS, Smith SK. Novel antiangiogenic agents for use in contraception. Contraception. 2005;71:263–71.

    Article  CAS  PubMed  Google Scholar 

  86. Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC, Taylor RN. Regulation of vascular endothelial growth factor (vegf) gene transcription by estrogen receptors alpha and beta. Proc Natl Acad Sci U S A. 2000;97:10972–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Okada H, Okamoto R, Tsuzuki T, Tsuji S, Yasuda K, Kanzaki H. Progestins inhibit estradiol-induced vascular endothelial growth factor and stromal cell-derived factor 1 in human endometrial stromal cells. Fertil Steril. 2011;96:786–91.

    Article  CAS  PubMed  Google Scholar 

  88. Smith OP, Critchley HO. Progestogen only contraception and endometrial break through bleeding. Angiogenesis. 2005;8:117–26.

    Article  CAS  PubMed  Google Scholar 

  89. Vereide AB, Kaino T, Sager G, Arnes M, Orbo A. Effect of levonorgestrel iud and oral medroxyprogesterone acetate on glandular and stromal progesterone receptors (pra and prb), and estrogen receptors (er-alpha and er-beta) in human endometrial hyperplasia. Gynecol Oncol. 2006;101:214–23.

    Article  CAS  PubMed  Google Scholar 

  90. Hanifi-Moghaddam P, Sijmons B, Ott MC, van Ijcken WF, Nowzari D, Kuhne EC, van der Spek P, Kloosterboer HJ, Burger CW, Blok LJ. The hormone replacement therapy drug tibolone acts very similar to medroxyprogesterone acetate in an estrogen-and progesterone-responsive endometrial cancer cell line. J Mol Endocrinol. 2006;37:405–13.

    Article  CAS  PubMed  Google Scholar 

  91. Conneely OM, Lydon JP. Progesterone receptors in reproduction: functional impact of the a and b isoforms. Steroids. 2000;65:571–7.

    Article  CAS  PubMed  Google Scholar 

  92. Nishigaki A, Okada H, Tsuzuki T, Cho H, Yasuda K, Kanzaki H. Angiopoietin 1 and angiopoietin 2 in follicular fluid of women undergoing a long protocol. Fertil Steril. 2011;96:1378–83.

    Article  CAS  PubMed  Google Scholar 

  93. Thurston G. Role of angiopoietins and tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis. Cell Tissue Res. 2003;314:61–8.

    Article  CAS  PubMed  Google Scholar 

  94. Thomas M, Augustin HG. The role of the angiopoietins in vascular morphogenesis. Angiogenesis. 2009;12:125–37.

    Article  CAS  PubMed  Google Scholar 

  95. Gale NW, Yancopoulos GD. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: vegfs, angiopoietins, and ephrins in vascular development. Genes Dev. 1999;13:1055–66.

    Article  CAS  PubMed  Google Scholar 

  96. Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos GD. Isolation of angiopoietin-1, a ligand for the tie2 receptor, by secretion-trap expression cloning. Cell. 1996;87:1161–9.

    Article  CAS  PubMed  Google Scholar 

  97. Hewett P, Nijjar S, Shams M, Morgan S, Gupta J, Ahmed A. Down-regulation of angiopoietin-1 expression in menorrhagia. Am J Pathol. 2002;160:773–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD. Angiopoietin-2, a natural antagonist for tie2 that disrupts in vivo angiogenesis. Science. 1997;277:55–60.

    Article  CAS  PubMed  Google Scholar 

  99. Khan AA, Sandhya VK, Singh P, Parthasarathy D, Kumar A, Advani J, Gattu R, Ranjit DV, Vaidyanathan R, Mathur PP, Prasad TS, Mac Gabhann F, Pandey A, Raju R, Gowda H. Signaling network map of endothelial tek tyrosine kinase. J Signal Transduct. 2014;2014:173026.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM, Yancopoulos GD. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med. 2000;6:460–3.

    Article  CAS  PubMed  Google Scholar 

  101. Hashizume H, Falcon BL, Kuroda T, Baluk P, Coxon A, Yu D, Bready JV, Oliner JD, McDonald DM. Complementary actions of inhibitors of angiopoietin-2 and vegf on tumor angiogenesis and growth. Cancer Res. 2010;70:2213–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Conde-Agudelo A, Papageorghiou AT, Kennedy SH, Villar J. Novel biomarkers for predicting intrauterine growth restriction: a systematic review and meta-analysis. BJOG. 2013;120:681–94.

    Article  CAS  PubMed  Google Scholar 

  103. Diamond JR, Wu B, Agarwal N, Bowles DW, Lam ET, Werner TL, Rasmussen E, Gamelin E, Soto F, Friberg G, Sun YN, Sharma S. Pharmacokinetic drug-drug interaction study of the angiopoietin-1/angiopoietin-2-inhibiting peptibody trebananib (amg 386) and paclitaxel in patients with advanced solid tumors. Invest New Drugs. 2015;33:691–9.

    Article  CAS  PubMed  Google Scholar 

  104. Goede V, Schmidt T, Kimmina S, Kozian D, Augustin HG. Analysis of blood vessel maturation processes during cyclic ovarian angiogenesis. Lab Invest. 1998;78:1385–94.

    CAS  PubMed  Google Scholar 

  105. Tsuzuki T, Okada H, Cho H, Shimoi K, Miyashiro H, Yasuda K, Kanzaki H. Divergent regulation of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor by hypoxia and female sex steroids in human endometrial stromal cells. Eur J Obstet Gynecol Reprod Biol. 2013;168:95–101.

    Article  CAS  PubMed  Google Scholar 

  106. Albrecht ED, Pepe GJ. Estrogen regulation of placental angiogenesis and fetal ovarian development during primate pregnancy. Int J Dev Biol. 2010;54:397–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Harfouche R, Echavarria R, Rabbani SA, Arakelian A, Hussein MA, Hussain SN. Estradiol-dependent regulation of angiopoietin expression in breast cancer cells. J Steroid Biochem Mol Biol. 2011;123:17–24.

    Article  CAS  PubMed  Google Scholar 

  108. Bonagura TW, Aberdeen GW, Babischkin JS, Koos RD, Pepe GJ, Albrecht ED. Divergent regulation of angiopoietin-1 and -2, tie-2, and thrombospondin-1 expression by estrogen in the baboon endometrium. Mol Reprod Dev. 2010;77:430–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Guo B, Wang W, Li SJ, Han YS, Zhang L, Zhang XM, Liu JX, Yue ZP. Differential expression and regulation of angiopoietin-2 in mouse uterus during preimplantation period. Anat Rec (Hoboken). 2011;295:338–46.

    Article  CAS  Google Scholar 

  110. Yang J, Jubb AM, Pike L, Buffa FM, Turley H, Baban D, Leek R, Gatter KC, Ragoussis J, Harris AL. The histone demethylase jmjd2b is regulated by estrogen receptor alpha and hypoxia, and is a key mediator of estrogen induced growth. Cancer Res. 2010;70:6456–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kazi AA, Molitoris KH, Koos RD. Estrogen rapidly activates the pi3k/akt pathway and hypoxia-inducible factor 1 and induces vascular endothelial growth factor a expression in luminal epithelial cells of the rat uterus. Biol Reprod. 2009;81:378–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Molitoris KH, Kazi AA, Koos RD. Inhibition of oxygen-induced hypoxia-inducible factor-1alpha degradation unmasks estradiol induction of vascular endothelial growth factor expression in ecc-1 cancer cells in vitro. Endocrinology. 2009;150:5405–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Burger JA, Kipps TJ. Cxcr4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107:1761–7.

    Article  CAS  PubMed  Google Scholar 

  114. Liekens S, Schols D, Hatse S. Cxcl12-cxcr4 axis in angiogenesis, metastasis and stem cell mobilization. Curr Pharm Des. 2010;16:3903–20.

    Article  CAS  PubMed  Google Scholar 

  115. Nishigaki A, Okada H, Okamoto R, Sugiyama S, Miyazaki K, Yasuda K, Kanzaki H. Concentrations of stromal cell-derived factor-1 and vascular endothelial growth factor in relation to the diameter of human follicles. Fertil Steril. 2011;95:742–6.

    Article  CAS  PubMed  Google Scholar 

  116. Salcedo R, Wasserman K, Young HA, Grimm MC, Howard OM, Anver MR, Kleinman HK, Murphy WJ, Oppenheim JJ. Vascular endothelial growth factor and basic fibroblast growth factor induce expression of cxcr4 on human endothelial cells: in vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol. 1999;154:1125–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Bachelder RE, Wendt MA, Mercurio AM. Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor cxcr4. Cancer Res. 2002;62:7203–6.

    CAS  PubMed  Google Scholar 

  118. Wu X, Jin LP, Yuan MM, Zhu Y, Wang MY, Li DJ. Human first-trimester trophoblast cells recruit cd56brightcd16- nk cells into decidua by way of expressing and secreting of cxcl12/stromal cell-derived factor 1. J Immunol. 2005;175:61–8.

    Article  CAS  PubMed  Google Scholar 

  119. Tsutsumi A, Okada H, Nakamoto T, Okamoto R, Yasuda K, Kanzaki H. Estrogen induces stromal cell-derived factor 1 (sdf-1/cxcl12) production in human endometrial stromal cells: a possible role of endometrial epithelial cell growth. Fertil Steril. 2011;95:444–7.

    Article  CAS  PubMed  Google Scholar 

  120. Takenaga K. Angiogenic signaling aberrantly induced by tumor hypoxia. Front Biosci (Landmark Ed). 2011;16:31–48.

    Article  CAS  Google Scholar 

  121. Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, Mantovani A, Melillo G, Sica A. Regulation of the chemokine receptor cxcr4 by hypoxia. J Exp Med. 2003;198:1391–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lukiw WJ, Ottlecz A, Lambrou G, Grueninger M, Finley J, Thompson HW, Bazan NG. Coordinate activation of hif-1 and nf-kappab DNA binding and cox-2 and vegf expression in retinal cells by hypoxia. Invest Ophthalmol Vis Sci. 2003;44:4163–70.

    Article  PubMed  Google Scholar 

  123. Martin G, Andriamanalijaona R, Grassel S, Dreier R, Mathy-Hartert M, Bogdanowicz P, Boumediene K, Henrotin Y, Bruckner P, Pujol JP. Effect of hypoxia and reoxygenation on gene expression and response to interleukin-1 in cultured articular chondrocytes. Arthritis Rheum. 2004;50:3549–60.

    Article  CAS  PubMed  Google Scholar 

  124. Kishimoto H, Wang Z, Bhat-Nakshatri P, Chang D, Clarke R, Nakshatri H. The p160 family coactivators regulate breast cancer cell proliferation and invasion through autocrine/paracrine activity of sdf-1alpha/cxcl12. Carcinogenesis. 2005;26:1706–15.

    Article  CAS  PubMed  Google Scholar 

  125. Strydom DJ. The angiogenins. Cell Mol Life Sci. 1998;54:811–24.

    Article  CAS  PubMed  Google Scholar 

  126. Koga K, Osuga Y, Tsutsumi O, Yano T, Yoshino O, Takai Y, Matsumi H, Hiroi H, Kugu K, Momoeda M, Fujiwara T, Taketani Y. Demonstration of angiogenin in human endometrium and its enhanced expression in endometrial tissues in the secretory phase and the decidua. J Clin Endocrinol Metab. 2001;86:5609–14.

    Article  CAS  PubMed  Google Scholar 

  127. Soufla G, Sifakis S, Spandidos DA. Fgf2 transcript levels are positively correlated with egf and igf-1 in the malignant endometrium. Cancer Lett. 2008;259:146–55.

    Article  CAS  PubMed  Google Scholar 

  128. Maruotti N, Cantatore FP, Crivellato E, Vacca A, Ribatti D. Angiogenesis in rheumatoid arthritis. Histol Histopathol. 2006;21:557–66.

    CAS  PubMed  Google Scholar 

  129. Shi N, Chen SY. Mechanisms simultaneously regulate smooth muscle proliferation and differentiation. J Biomed Res. 2014;28:40–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Betsholtz C. Insight into the physiological functions of pdgf through genetic studies in mice. Cytokine Growth Factor Rev. 2004;15:215–28.

    Article  CAS  PubMed  Google Scholar 

  131. Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in pdgf-b-deficient mice. Science. 1997;277:242–5.

    Article  CAS  PubMed  Google Scholar 

  132. Lash GE, Innes BA, Drury JA, Robson SC, Quenby S, Bulmer JN. Localization of angiogenic growth factors and their receptors in the human endometrium throughout the menstrual cycle and in recurrent miscarriage. Hum Reprod. 2012;27:183–95.

    Article  CAS  PubMed  Google Scholar 

  133. Dai H, Zhao S, Xu L, Chen A, Dai S. Expression of efp, vegf and bfgf in normal, hyperplastic and malignant endometrial tissue. Oncol Rep. 2010;23:795–9.

    CAS  PubMed  Google Scholar 

  134. Evans J, Catalano RD, Brown P, Sherwin R, Critchley HO, Fazleabas AT, Jabbour HN. Prokineticin 1 mediates fetal-maternal dialogue regulating endometrial leukemia inhibitory factor. FASEB J. 2009;23:2165–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Ngan ES, Lee KY, Yeung WS, Ngan HY, Ng EH, Ho PC. Endocrine gland-derived vascular endothelial growth factor is expressed in human peri-implantation endometrium, but not in endometrial carcinoma. Endocrinology. 2006;147:88–95.

    Article  CAS  PubMed  Google Scholar 

  136. Battersby S, Critchley HO, Morgan K, Millar RP, Jabbour HN. Expression and regulation of the prokineticins (endocrine gland-derived vascular endothelial growth factor and bv8) and their receptors in the human endometrium across the menstrual cycle. J Clin Endocrinol Metab. 2004;89:2463–9.

    Article  CAS  PubMed  Google Scholar 

  137. Becker CM, Sampson DA, Short SM, Javaherian K, Folkman J, D’Amato RJ. Short synthetic endostatin peptides inhibit endothelial migration in vitro and endometriosis in a mouse model. Fertil Steril. 2006;85:71–7.

    Article  CAS  PubMed  Google Scholar 

  138. Cui R, Takahashi K, Takahashi F, Tanabe KK, Fukuchi Y. Endostatin gene transfer in murine lung carcinoma cells induces vascular endothelial growth factor secretion resulting in up-regulation of in vivo tumorigenecity. Cancer Lett. 2006;232:262–71.

    Article  CAS  PubMed  Google Scholar 

  139. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88:277–85.

    Article  PubMed  Google Scholar 

  140. Fu GF, Li X, Hou YY, Fan YR, Liu WH, Xu GX. Bifidobacterium longum as an oral delivery system of endostatin for gene therapy on solid liver cancer. Cancer Gene Ther. 2005;12:133–40.

    Article  CAS  PubMed  Google Scholar 

  141. Pollheimer J, Bauer S, Huber A, Husslein P, Aplin JD, Knofler M. Expression pattern of collagen xviii and its cleavage product, the angiogenesis inhibitor endostatin, at the fetal-maternal interface. Placenta. 2004;25:770–9.

    Article  CAS  PubMed  Google Scholar 

  142. Nasu K, Nishida M, Fukuda J, Kawano Y, Nishida Y, Miyakawa I. Hypoxia simultaneously inhibits endostatin production and stimulates vascular endothelial growth factor production by cultured human endometrial stromal cells. Fertil Steril. 2004;82:756–9.

    Article  CAS  PubMed  Google Scholar 

  143. Bass R, Fernandez AM, Ellis V. Maspin inhibits cell migration in the absence of protease inhibitory activity. J Biol Chem. 2002;277:46845–8.

    Article  CAS  PubMed  Google Scholar 

  144. Abraham S, Zhang W, Greenberg N, Zhang M. Maspin functions as tumor suppressor by increasing cell adhesion to extracellular matrix in prostate tumor cells. J Urol. 2003;169:1157–61.

    Article  CAS  PubMed  Google Scholar 

  145. Huang Y, Cai LW, Yang R. Expression of maspin in the early pregnant mouse endometrium and its role during embryonic implantation. Comp Med. 2012;62:179–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Zaslavsky A, Baek KH, Lynch RC, Short S, Grillo J, Folkman J, Italiano Jr JE, Ryeom S. Platelet-derived thrombospondin-1 is a critical negative regulator and potential biomarker of angiogenesis. Blood. 2010;115:4605–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Nakamura DS, Edwards AK, Ahn SH, Thomas R, Tayade C. Compatibility of a novel thrombospondin-1 analog with fertility and pregnancy in a xenograft mouse model of endometriosis. PLoS One. 2015;10, e0121545.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Seki N, Kodama J, Hashimoto I, Hongo A, Yoshinouchi M, Kudo T. Thrombospondin-1 and -2 messenger rna expression in normal and neoplastic endometrial tissues: correlation with angiogenesis and prognosis. Int J Oncol. 2001;19:305–10.

    CAS  PubMed  Google Scholar 

  149. Tan XJ, Lang JH, Zheng WM, Leng JH, Zhu L. Ovarian steroid hormones differentially regulate thrombospondin-1 expression in cultured endometrial stromal cells: implications for endometriosis. Fertil Steril. 2010;93:328–31.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Kansai Medical University, 2-5-1 shinmachi-cho, Hirakata, Osaka, 573-1010, Japan

    Hidetaka Okada, Tomoko Tsuzuki, Hiromi Murata, Atsushi Kasamatsu, Tomoo Yoshimura & Hideharu Kanzaki

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  1. Hidetaka Okada
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  2. Tomoko Tsuzuki
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    Hideharu Kanzaki

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Okada, H., Tsuzuki, T., Murata, H., Kasamatsu, A., Yoshimura, T., Kanzaki, H. (2016). Regulation of Angiogenesis in the Human Endometrium. In: Kanzaki, H. (eds) Uterine Endometrial Function. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55972-6_6

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