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Vascular morphogenesis in the primate ovary

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Abstract

Ovarian function is dependent on intense cyclical vascular morphogenesis and regression. The molecular and cellular pathways involved in the generation of new capillary networks in the ovary are now being elucidated. Focussing on the marmoset, the course of angiogenesis at different stages of follicular maturation and in the corpus luteum throughout the cycle and in early pregnancy have been quantified and major progress has been made in the evaluation of the role of vascular endothelial growth factor (VEGF). To study the physiological role of VEGF in follicular and luteal angiogenesis in detail, VEGF was inhibited during defined stages of the cycle in vivo. VEGF antagonist administered throughout the follicular phase of the cycle resulted in a marked decrease in endothelial cell proliferation in developing antral follicles, accompanied by a decline in granulosa cell proliferation, restriction of follicular growth and inhibition of ovulation. An outstanding feature in the ovary is the intense angiogenesis that occurs during the early luteal phase. VEGF inhibitors markedly suppressed this angiogenesis, resulting in a marked restriction in the development of the microvascular tree and suppression of plasma progesterone. These studies showed that VEGF is essential for normal follicular and luteal angiogenesis and function, and demonstrated how luteal angiogenesis in particular could serve as a sensitive bioassay for putative angiogenic antagonists. Antagonists of VEGF are potent tools for investigating the role of angiogenic factors within the ovary and may have applications to the treatment of reproductive disorders characterised by alterations in normal vascular structure or function.

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Abbreviations

Ang-1 and Ang-2:

angiopoietin-1 and -2

BrdU:

bromodeoxyuridine

CTGF:

connective tissue growth factor

EG-VEGF:

endocrine gland-VEGF

hCG:

human chorionic gonadotrophin

PlGF:

placental growth factor

VEGF:

vascular endothelial growth factor

References

  1. Folkman J. Angiogenesis in female reproductive organs. In: Alexander NJ, D’Arcangues C (eds): Steroid Hormones and Uterine Bleeding. Washington DC: AAAS Press 1992; 143–58.

    Google Scholar 

  2. Reynolds LP, Killilea SD, Redmer DA. Angiogenesis in the female reproductive system. FASEB Journal 1992;6:886–92

    PubMed  CAS  Google Scholar 

  3. Shweiki D, Itin A, Neufeld G, Gitay-Goren H, Keshet E. Patterns of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest 1993;91:2235–43

    Article  PubMed  CAS  Google Scholar 

  4. Wiegand SJ, Boland P, Yancopoulos D (2000) Cooperative roles of the angiopoietins and vascular endothelial growth factor in ovarian angiogenesis. In: Adashi EY, (ed) Ovulation evolving scientific and clinical concepts. Springer-Verlag, New York, pp. 175–86

    Google Scholar 

  5. Balakier H, Stronell RD. Colour Doppler assessment of folliculogenesis in in vitro fertilization patients. Fertil Steril 1994;62:1211–6

    PubMed  CAS  Google Scholar 

  6. Campbell S, Bourne TH, Waterstone J, Reynolds KM, Crayford TJ, Jurkovoc D, et al. Transvaginal colour blood flow imaging of the periovulatory follicle. Fertil Steril 1993;60:433–8

    PubMed  CAS  Google Scholar 

  7. Wulff C, Wiegand SJ, Saunders PTK, Scobie GA, Fraser HM. Angiogenesis during folliular development in the primate and its inhibition by treatment with truncated Flt-1Fc (vascular endothelial growth factor trapA40). Endocrinology 2001;142:3244–54

    Article  PubMed  CAS  Google Scholar 

  8. Fraser HM, Lunn SF. (1999) Non human primates in female reproductive medicine. In: Weinbauer GF, Korte R, (eds), Reproduction in Nonhuman Primates : A model system for human reproductive physiology and toxicology. Waxmann Verlag, New York, pp. 27–59

    Google Scholar 

  9. Fraser HM, Groome NP, McNeilly AS. Follicle stimulating hormone-inhibin B interactions during the follicular phase of the primate menstrual cycle revealed by GnRH antagonist and anti-estrogen treatment. J Clin Endocrinol Metab 1999;84:1365–9

    Article  PubMed  CAS  Google Scholar 

  10. Wulff C, Wilson H, Wiegand SJ, Rudge JS, Fraser HM. Prevention of thecal angiogenesis, antral follicular growth, and ovulation in the primate by treatment with vascular endothelial growth factor trap R1R2. Endocrinology 2002;143:2797–807

    Article  PubMed  CAS  Google Scholar 

  11. Fraser HM, Wulff C. Angiogenesis in the primate ovary. Reprod Fertil Dev 2001;13:557–66

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Taylor PD, Hillier SG, Fraser HM. Effects of GnRH antagonist treatment on follicular development and angiogenesis in the primate ovary. J Endocrinol 2004;183: 1–17

    Article  PubMed  CAS  Google Scholar 

  14. Hazzard TM, Molskness T, Chaffin C, Stouffer RL. Vascular endothelial growth factor (VEGF) and angiopoietin regulation by gonadotrophin and steroids in macaque granulosa cells during the peri-ovulatory interval. Mol Hum Reprod 1999;5:1115–21

    Article  PubMed  CAS  Google Scholar 

  15. Hazzard TM, Stouffer RL,. Angiogenesis in ovarian follicular and luteal development. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:883–900

    Article  PubMed  CAS  Google Scholar 

  16. Martinez-Chequer JC, Stouffer RL, Hazzard TM, Patton PE, Molskeness TA. Insulin-like growth factors-1 and –2, but not hypoxia, synergize with gonadotropin hormone to promote vascular endothelial growth factor-A secretion by monkey granolosa cells from preovulatory follicles. Biol Reprod 2003;68:1112–8

    Article  PubMed  CAS  Google Scholar 

  17. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997;277:55–60

    Article  PubMed  CAS  Google Scholar 

  18. Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002;20:4368–80

    Article  PubMed  CAS  Google Scholar 

  19. Zeleznik AJ, Schuler HM, Reichert LJ. Gonadotropin-binding sites in the rhesus monkey ovary: role of the vasculature in the selective distribution of human chorionic gonadotropin to the preovulatory follicle. Endocrinology 1981;109:356–62

    Article  PubMed  CAS  Google Scholar 

  20. Koos RD. Increased expression of vascular endothelial growth permeability factor in the rat ovary following an ovulatory gonadotropin stimulus: Potential roles in follicle rupture. Biol Reprod 1995;52:1426–35

    Article  PubMed  CAS  Google Scholar 

  21. Thurston G. Role of Angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis. Cell Tissue Res 2003;314:61–8

    Article  PubMed  CAS  Google Scholar 

  22. LeCouter J, Kowalski J, Foster J, Hass P, Zhang Z, Dillard-Telm L, et al. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 2001;412:877–84

    Article  PubMed  CAS  Google Scholar 

  23. Li M, Bullock CM, Knauer DJ, Ehlert FJ, Zhou QY. Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle. Mol Pharmacol 2001;59:692–8

    PubMed  CAS  Google Scholar 

  24. Ferrara N, Frantz G, LeCouter J, Dillard-Telm L, Pham T, Draksharapu A, et al. Differential expression of the angiogenic factor genes vascular endothelial growth factor (VEGF) and endocrine gland-derived VEGF in normal and polycystic human ovaries. Am J Pathol 2003;162:1881–93

    PubMed  CAS  Google Scholar 

  25. Kisliouk T, Levy N, Hurwitz A, Meidan R. Presence and regulation of endocrine gland vascular endothelial growth factor/prokineticin-1 and its receptors in ovarian cells. J Clin Endocrinol Metab 2003;88:3700–7

    Article  PubMed  CAS  Google Scholar 

  26. Greenaway J, Connor K, Pedersen HG, Coomer BL, Lamarre J, Petrik J. Vascular endothelial growth factor and its receptor, Flk-1/KDR, are cytoprotective in the extravascular compartment of the ovarian follicle. Endocrinology 2004; 145:2896–905

    Article  PubMed  CAS  Google Scholar 

  27. Klauber N, Rohan RM, Flynn E, D’Amato RJ. Critical components of the female reproductive pathway are suppressed by the angiogenesis inhibitor AGM-1470. Nat Med 1997; 3: 443–6

    Article  PubMed  CAS  Google Scholar 

  28. Fraser HM, Dickson SE, Morris KD, Erickson GF, Lunn SF. The effects of the angiogenesis inhibitor TNP-470 on luteal establishment and function in the primate. Hum Reprod 1999;14:2054–60

    Article  PubMed  CAS  Google Scholar 

  29. Zimmermann RC, Xiao E, Husami N, Sauer MV, Lobo R, Kitajewski J, et al. Short-term administration of antivascular endothelial growth factor antibody in the late follicular phase delays follicular development in the rhesus monkey. J Clin Endocrinol Metab 2001;86:768–72

    Article  PubMed  CAS  Google Scholar 

  30. Zimmermann RC, Xiao E, Bohlen P, Ferin M. Administration of antivascular endothelial growth factor receptor 2 antibody in the early follicular phase delays follicular selection and development in the rhesus monkey. Endocinol 2002;143:2496–502

    Article  PubMed  CAS  Google Scholar 

  31. Gomez R, Simon C, Remohi J, Pellicer A. Vascular endothelial growth factor receptor-2 activation induces vascular permeability in hyperstimulated rats, and this effect is prevented by receptor blockade. Endocrinol 2002;143:4339–48

    Article  PubMed  CAS  Google Scholar 

  32. Ferrara N, Chen H, Davis-Smyth T, Geber H-P, Nguyen T-N, Peers D, et al. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med 1998;4(3):336–40

    Article  PubMed  CAS  Google Scholar 

  33. Hazzard TM, Xu F, Stouffer RL. Injection of soluble vascular endothelial growth factor receptor 1 into the preovulatory follicle disrupts ovulation and subsequent luteal funaction in rhesus monkeys. Biol Reprod 2002;67:1305–12

    Article  PubMed  CAS  Google Scholar 

  34. Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002;99:11393–8

    Article  PubMed  CAS  Google Scholar 

  35. Hazzard TM, Rohan RM, Molskness TA, Fanton JW, D’Amato RJ, Stouffer RL. Injection of antiangiogenic agents into the macaque preovulatory follicle: disruption of corpus luteum development and function. Endocrine 2002;17:199–206

    Article  PubMed  CAS  Google Scholar 

  36. Fraser HM, Dickson SE, Lunn SF, Wulff C, Morris KD, Carroll V, et al. Suppression of luteal angiogenesis in the primate after neutralization of vascular endothelial growth factor. Endocrinol 2000;141:995–1000

    Article  PubMed  CAS  Google Scholar 

  37. Wulff C, Wilson H, Rudge JS, Wiegand SJ, Lunn SF, Fraser HM. Luteal angiogenesis: prevention and intervention by treatment with vascular endothelial growth factor trap A40. J Clin Endocrinol Metab 2001;86:3377–86

    Article  PubMed  CAS  Google Scholar 

  38. Taylor PD, Hillier SG, Fraser HM. The role of vascular endothelial growth factor in dominant follicle selection, expansion, and ovulation in the marmoset. Biol Reprod 2004; Program for the 37th Annual Meeting of the Society for the Study of Reproduction: Abstr 587

  39. Xu F, Stouffer RL. Local delivery of angiopoietin-2 into the preovulatory follicle terminates the menstrual cycle in rhesus monkeys. Biol Reprod 2004; Program for the 37th Annual Meeting of the Society for the Study of Reproduction: Abstr 20

  40. Danforth DR, Schroeder A, Arbogast LK, Pravin TP. Vascular endothelial growth factor (VEGF) is essential for primordial follicle survival. Soc Gynecol Invest 2003;10(Number 2 (Supplement)):673

    Google Scholar 

  41. Danforth DR, Arbogast LK, Ghosh S, Dickerman A, Rofagha R, Friedman CI. Vascular endothelial growth factor stimulates preantral follicle growth in the rat ovary. Biol Reprod 2003;68:1736–41

    Article  PubMed  CAS  Google Scholar 

  42. Danforth DR, Roberts A, Arbogast LK, Friedman CI. Follicular preservation during cyclophosphamide treatment: GnRH agonist vs. antagonist. Soc Gynecol Invest 2003; 10(2 Suppl): 136

    Google Scholar 

  43. Fraser HM, Wilson H, Rudge JS, Wiegand SJ. Single injections of vascular endothelial growth factor trap block ovulation in the macaque, and produce a prolonged, dose-related suppression of ovarian function. J Clin Endocrinol Metab 2005; 90: 1114–22

    Google Scholar 

  44. Zimmermann RC, Hartman T, Kavic S, Pauli SA, Bohlen P, Sauer MV, et al. Vascular endothelial growth factor receptor 2-mediated angiogenesis is essential for gonadotropin-dependent follicle development. J Clin Invest 2003;112:659–69

    Article  PubMed  CAS  Google Scholar 

  45. Augustin HG (2000) Development of the vascular sytem of the corpus luteum. In: Risau W, (eds) Morphogenesis of Endothelium. Harwood Academic Publishers, Reading U.K, pp. 237–54

    Google Scholar 

  46. Eberhard AE, Kahlert S, Goede V, Hemmerlin B, Plate KH, Augustin HG. Heterogeneity of angiogenesis and blood vessel maturation in human tumours: implications for antiangiogenic tumor therapies. Can Res 2000;60:1388–93

    CAS  Google Scholar 

  47. Wulff C, Dickson SE, Duncan WC, Fraser HM. Angiogenesis in the human corpus luteum: simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization. Hum Reprod 2001;16:2515–24

    Article  PubMed  CAS  Google Scholar 

  48. Dickson SE, Fraser HM. Inhibition of early luteal angiogenesis by gonadotropin-releasing hormone antagonist treatment in the primate. J Clin Endocrinol Metab 2000;85:2339–44

    Article  PubMed  CAS  Google Scholar 

  49. Young FM, Rodger FE, Illingworth PJ, Fraser HM. Cell proliferation and vascular morphology in the marmoset corpus luteum. Hum Reprod 2000;15:557–66

    Article  PubMed  CAS  Google Scholar 

  50. Christenson LK, Stouffer RL. Proliferation of microvascular endothelial cells in the primate corpus luteum during the menstrual cycle and simulated early pregnancy. Endocrinology 1996;137:367–74

    Article  PubMed  CAS  Google Scholar 

  51. Jablonka-Shariff A, Grazul-Bilska AT, Redmer DA, Reynolds LP. Growth and cellular proliferation of ovine corpora lutea throughout the estrous cycle. Endocrinol 1993;133:1871–9

    Article  PubMed  CAS  Google Scholar 

  52. Al-Zi’abi MO, Watson ED, Fraser HM. Angiogenesis and vascular endothelial growth factor expression in the equine corpus luteum. Reproduction 2003;125:259–70

    Article  PubMed  CAS  Google Scholar 

  53. Wulff C, Wilson H, Largue P, Duncan WC, Armstrong D, Fraser HM. Angiogenesis in the human corpus luteum: Localization and changes in angiopoietins, Tie-2 and vascular endothelial growth factor messenger ribonucleic acid. J Clin Endocrinol Metab 2000;85:4302–9

    Article  PubMed  CAS  Google Scholar 

  54. Rowe AJ, Morris KD, Bicknell R, Fraser HM. Angiogenesis in the corpus luteum of early pregnancy in the marmoset and the effects of vascular endothelial growth factor immunoneutrlaization on establishment of pregnancy. Biol Reprod 2002;67:1180–8

    Article  PubMed  CAS  Google Scholar 

  55. Fraser HM, Bell J, Wilson H et al. Localisation and quantification of endocrine gland vascular endothelial growth factor in the human corpus luteum. J Clin Endocrinol Metab 2005; 90: 427–34

    Google Scholar 

  56. Fraser HM, Lunn SF, Kim H, Duncan WC, Rodger FE, Illingworth PJ, et al. Changes in insulin-like growth factor binding protein-3 mRNA expression in endothelial cells of the human corpus luteum: a possible role in luteal development and rescue. J Clin Endocrinol Metab 2000;85:1672–7

    Article  PubMed  CAS  Google Scholar 

  57. Fraser HM, Lunn SF, Kim H, Erickson GF. Insulin-like growth factor binding protein-3 IGFBP-3) mRNA in the endothelial cells of the primate corpus luteum. Hum Reprod 1998;13:2180–5

    Article  PubMed  CAS  Google Scholar 

  58. Duncan WC, Hillier SG, Gay E et al. Connective tissue growth factor (CTGF) expression in human luteal cells: Evidence of paracrine action. J Clin Endocrinol Metab 2005

  59. Aston KE, O’Sullivan MJB, Thomas EJ, Richardson MC. Effect of human chorionic gonadotrophin on the detachment of human granulosa cells from extracellular matrix layered onto glass or plastic. Hum Reprod 1996;11:336–40

    PubMed  CAS  Google Scholar 

  60. Christenson LK, Stouffer RL. Isolation and culture of microvascular endothelial cells from the primate corpus luteum. Biol Reprod 1996;55:1397–404

    Article  PubMed  CAS  Google Scholar 

  61. Ratcliffe KE, Anthony FW, Richardson MC, Stones RW. Morphology and functional charactertics of human ovarian microvascular endothelium. Hum Reprod 1999;14:1549–54

    Article  PubMed  CAS  Google Scholar 

  62. Dickson SE, Bicknell R, Fraser HM. Mid-luteal angiogenesis and function in the primate is dependent on vascular endothelial growth factor. J Endocrinol 2001;168:409–16

    Article  PubMed  CAS  Google Scholar 

  63. Modlich UFJ, Kaup HG, Augustin HG. Cyclic angiogenesis and blood vessel regression in the ovary during luteolysis involves endothelial detachment and vessel occlusion. Lab Invest 1996; 74:771–80

    PubMed  CAS  Google Scholar 

  64. Wang TH, Horng SG, Chang CL, Wu HM, Tsai YJ, Wang HS, et al. Human chorionic gonadotropin-induced ovarian hyperstimulation syndrome is associated with up-regulation of vascular endothelial growth factor. J Clin Endocrinol Metab 2002;87(7):3300–8

    Article  PubMed  CAS  Google Scholar 

  65. Gonzalez-Mariscal L, Betanoz A, Nava P, Jaramillo BE. Tight junction proteins. Prog Biophys Mol Biol 2003;81:1–44

    Article  PubMed  CAS  Google Scholar 

  66. Wulff C, Fraser HM, Duncan WC et al. Evidence that tight junction proteins (occludin, claudin-1 and 2) are involved in regulation of permeability in the human corpus luteum. Biol Reprod 2004; Program for the 37th Annual Meeting of the Society for the Study of Reproduction: Abstr 801

  67. Dvorak HF, Nagy JA, Feng D, Brown LF, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hypermeability in angiogenesis. Curr Top Microbiol Immunol. 1999;237:97–132

    PubMed  CAS  Google Scholar 

  68. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004; 3: 391–400

    Google Scholar 

  69. Shimizu T, Jiang JY, Iijima K, Miyabayashi K, Ogawa Y, Sasada H, et al. Induction of follicular development by direct single injection of vascular endothelial growth factor gene fragments into the ovary of miniature gilts. Biol Reprod 2003;69:1388–93

    Article  PubMed  CAS  Google Scholar 

  70. Erickson GF. The ovarian connection. In Aashi EY, Rock JA, Rosenwaks Z (eds): Reproductive Endocrinology, Surgery and Technology. Philadelphia: Lippincott-Raven Publishers 1996; 1142–60

    Google Scholar 

  71. Abbott DH, Dumesic DA, Franks S. Developmental origin of polycystic ovary syndrome - a hypothesis. J Endocrinol 2002;174:1–5

    Article  PubMed  CAS  Google Scholar 

  72. Pan HA, Wu MH, Cheng YC, Li CH, Chang FM. Quantification of Doppler signal in polycystic ovary syndrome using three-dimensional power Doppler ultrasonography: a possible new marker for diagnosis. Hum Reprod 2002;17:201–6

    Article  PubMed  Google Scholar 

  73. Kamat BR, Brown LF, Manseau EJ, Senger DR, Dvorak HF. Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells. Am J Path 1995;146:157–5

    PubMed  CAS  Google Scholar 

  74. Pellicer A, Albert C, Mercader A, Bonilla-Mussoles F, Remohi J, Simon C. The pathogenesis of ovarian hyperstimulation syndrome: in vivo studies investigating the role of interleukin (IL)-1beta and vascular endithelial growth factor. Fertil Steril 1999;7:482–9

    Article  Google Scholar 

  75. Albert C, Garrido N, Mercader A et al. The role of endothelial cells in the pathogenesis of ovarian hyperstimulation syndrome. Mol Hum Reprod 2002; 8: 409–18

    Article  PubMed  CAS  Google Scholar 

  76. Byrne AT, Ross L, Holash J, Nakanishi M, Hu L, Hofmann JI, et al. Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodelling in an ovarian cancer model. Clin Cancer Res 2003;9:5721–8

    PubMed  CAS  Google Scholar 

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Acknowledgements

We thank our collaborators, Dr Christine Wulff, Dr Stanley J. Wiegand, Dr John Rudge, Dr Roy Bicknell and graduate students Dr Sarah Dickson, Dr Amanda Rowe and Dr Paul Taylor for their contributions to the studies reviewed in this paper. We are grateful to Regeneron Pharmaceuticals, Tarrytown, NY, for provision of VEGF Traps.

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Authors and Affiliations

  1. MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Edinburgh, UK

    Hamish M. Fraser

  2. Department of Reproductive and Developmental Sciences, Centre for Reproductive Biology, Edinburgh, UK

    W. Colin Duncan

  3. MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The University of Edinburgh Chancellor’s Building, Edinburgh, UK

    Hamish M. Fraser

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Correspondence to Hamish M. Fraser.

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Fraser, H.M., Duncan, W.C. Vascular morphogenesis in the primate ovary. Angiogenesis 8, 101–116 (2005). https://doi.org/10.1007/s10456-005-9004-y

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