Angiogenesis

, Volume 14, Issue 4, pp 523–532 | Cite as

Prednisolone treatment reduces endometrial spiral artery development in women with recurrent miscarriage

  • Gendie E. Lash
  • Judith N. Bulmer
  • Barbara A. Innes
  • Josephine A. Drury
  • Stephen C. Robson
  • Siobhan Quenby
Original Paper

Abstract

Background

Uterine natural killer (uNK) cells and endometrial blood vessel maturation are increased in the luteal phase of the menstrual cycle in a subset of women with recurrent miscarriage (RM). uNK cell numbers are reduced after treatment with prednisolone (20 mg/day for 3 weeks).

Hypotheses

Prednisolone treatment reduces endometrial vascular maturation and angiogenic growth factor expression in women with RM with increased uNK cells.

Methods

Endometrial biopsies (n = 18 paired samples) from women with RM at LH + 7 before and during prednisolone treatment (20 mg/day for 3 weeks) were snap frozen. Total RNA and cDNA was prepared and used in a human angiogenesis RT-PCR superarray (84 genes, n = 6 pairs) with results validated using RT-PCR (n = 15 pairs). Immunohistochemistry (n = 15 pairs) was performed for Factor VIII, α-smooth muscle actin (α-SMA) and myosin heavy chain (MyHC) and the total number of vessels and the percentage of vessels completely surrounded by vascular smooth muscle cells (VSMCs) were determined.

Results

During prednisolone treatment there was no change in the total number of endometrial blood vessels but the percentage of vessels completely surrounded by VSMCs was decreased (α-SMA P < 0.0001; MyHC P < 0.0001). Endometrial EGF and STAB 1 expression was decreased during prednisolone treatment in samples from woman who went on to have a live birth.

Conclusions

The effect of prednisolone therapy for some women with RM may be due to altered endometrial angiogenic growth factor expression and reduced blood vessel maturation.

Keywords

Recurrent miscarriage Vascular development Prednisolone uNK cells Macrophages 

Notes

Acknowledgments

This work was supported by a Research Grant from The Royal Society. GEL was a Newcastle University, Faculty of Medicine Research Fellow.

Conflict of interest

None of the authors have any conflict of interest.

References

  1. 1.
    Rogers PA, Abberton KM (2003) Endometrial arteriogenesis: vascular smooth muscle cell proliferation and differentiation during the menstrual cycle and changes associated with endometrial bleeding disorders. Microsc Res Tech 60:412–419PubMedCrossRefGoogle Scholar
  2. 2.
    Girling JE, Rogers PAW (2005) Recent advances in endometrial angiogenesis research. Angiogenesis 8:89–99PubMedCrossRefGoogle Scholar
  3. 3.
    Rzucidlo EM, Martin KA, Powell RJ (2007) Regulation of vascular smooth muscle cell differentiation. J Vasc Surg 45:25A–32ACrossRefGoogle Scholar
  4. 4.
    Quenby S, Farquharson RG (1993) Predicting recurring miscarriage: what is important? Obstet Gynecol 82:132–138PubMedGoogle Scholar
  5. 5.
    Rai R, Regan L (2006) Recurrent miscarriage. Lancet 368:601–611PubMedCrossRefGoogle Scholar
  6. 6.
    Brosens JJ, Gellersen B (2010) Something new about early pregnancy: decidual biosensoring and natural embryo selection. Ultrasound Obstet Gynecol 36:1–5PubMedCrossRefGoogle Scholar
  7. 7.
    Teklenburg G, Salker M, Molokhia M, Lavery S, Trew G, Aojanepong T, Mardon HJ, Lokugamage AU, Rai R, Landles C, Roelen BA, Quenby S, Kuijk EW, Kavelaars A, Heijnen CJ, Regan L, Brosens JJ, Macklon NS (2010) Natural selection of human embryos: decidualizing endometrial stromal cells serve as sensors of embryo quality upon implantation. PLoS One 5:e10258PubMedCrossRefGoogle Scholar
  8. 8.
    Salker M, Teklenburg G, Molokhia M, Lavery S, Trew G, Aojanepong T, Mardon HJ, Lokugamage AU, Rai R, Landles C, Roelen BA, Quenby S, Kuijk EW, Kavelaars A, Heijnen CJ, Regan L, Macklon NS, Brosens JJ (2010) Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss. PLoS One 5:e10287PubMedCrossRefGoogle Scholar
  9. 9.
    Quenby S, Farquharson R, Young M, Vince G (2003) Successful pregnancy outcome following 19 consecutive miscarriages: case report. Hum Reprod 18:2562–2564PubMedCrossRefGoogle Scholar
  10. 10.
    Habara T, Nakatsuka M, Konishi H, Asagiri K, Noguchi S, Kudo T (2002) Elevated blood flow resistance in uterine arteries of women with unexplained recurrent pregnancy loss. Hum Reprod 17:190–194PubMedCrossRefGoogle Scholar
  11. 11.
    Quenby S, Nik H, Innes B, Lash G, Turner M, Drury J, Bulmer J (2009) Uterine natural killer cells and angiogenesis in recurrent reproductive failure. Hum Reprod 24:45–54PubMedCrossRefGoogle Scholar
  12. 12.
    Goswamy RK, Williams G, Steptoe PC (1988) Decreased uterine perfusion—a cause of infertility. Hum Reprod 3:955–959PubMedGoogle Scholar
  13. 13.
    Steer CV, Tan SL, Mason BA, Campbell S (1994) Midluteal-phase vaginal color Doppler assessment of uterine artery impedance in a subfertile population. Fertil Steril 61:53–58PubMedGoogle Scholar
  14. 14.
    Yedwab GA, Paz G, Homonnai TZ, David MP, Kraicer PF (1976) The temperature, pH, and partial pressure of oxygen in the cervix and uterus of women and uterus of rats during the cycle. Fertil Steril 27:304–309PubMedGoogle Scholar
  15. 15.
    Rodesch F, Simon P, Donner C, Jauniaux E (1992) Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol 80:283–285PubMedGoogle Scholar
  16. 16.
    Jauniaux E, Watson AL, Hempstock J, Bao Y-P, Skepper JN, Burton GJ (2000) Onset of maternal arterial blood flow and placental oxidative stress: a possible factor in human early pregnancy failure. Am J Pathol 157:2111–2122PubMedCrossRefGoogle Scholar
  17. 17.
    Hung TH, Skepper JN, Burton GJ (2001) In vitro ischemia–reperfusion injury in term human placenta as a model for oxidative stress in pathological pregnancies. Am J Pathol 159:1031–1043PubMedCrossRefGoogle Scholar
  18. 18.
    Hustin J, Jauniaux E, Schaaps JP (1990) Histological study of the materno-embryonic interface in spontaneous abortion. Placenta 11:477–486PubMedCrossRefGoogle Scholar
  19. 19.
    Lash GE, Robson SC, Bulmer JN (2010) Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua. Placenta 31:S87–S92PubMedCrossRefGoogle Scholar
  20. 20.
    Clifford K, Flanagan AM, Regan L (1999) Endometrial CD56þ natural killer cells in women with recurrent miscarriage: a histomorphometric study. Hum Reprod 14:2727–2730PubMedCrossRefGoogle Scholar
  21. 21.
    Quenby S, Bates M, Doig T, Brewster J, Lewis-Jones DI, Johnson PM, Vince G (1999) Pre-implantation endometrial leukocytes in women with recurrent miscarriage. Hum Reprod 14:2386–2391PubMedCrossRefGoogle Scholar
  22. 22.
    Quenby S, Kalumbi C, Bates M, Farquharson RG, Vince G (2005) Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage. Fertil Steril 84:980–984PubMedCrossRefGoogle Scholar
  23. 23.
    Quenby S, Farquharson R (2006) Uterine natural killer cells, implantation failure and recurrent miscarriage. Reprod Biomed Online 13:24–28PubMedCrossRefGoogle Scholar
  24. 24.
    Tuckerman E, Laird SM, Prakash A, Li TC (2007) Prognostic value of the measurement of uterine natural killer cells in the endometrium of women with recurrent miscarriage. Hum Reprod 22:2208–2213PubMedCrossRefGoogle Scholar
  25. 25.
    Rogers PAW (1996) Structure and function of endometrial blood vessels. Hum Reprod Update 2:57–62PubMedCrossRefGoogle Scholar
  26. 26.
    Banciu M, Schiffelers RM, Fens MH, Metselaar JM, Storm G (2006) Anti-angiogenic effects of liposomal prednisolone phosphate on B16 melanoma in mice. J Control Release 113:1–8PubMedCrossRefGoogle Scholar
  27. 27.
    Banciu M, Metselaar JM, Schiffelers RM, Storm G (2008) Liposomal glucocorticoids as tumor-targeted anti-angiogenic nanomedicine in B16 melanoma-bearing mice. J Steroid Biochem Mol Biol 111:101–110PubMedCrossRefGoogle Scholar
  28. 28.
    Feltis BN, Wignarajah D, Reid DW, Ward C, Harding R, Walters EH (2007) Effects of inhaled fluticasone on angiogenesis and vascular endothelial growth factor in asthma. Thorax 62:314–319PubMedCrossRefGoogle Scholar
  29. 29.
    Ehrmantraut S, Laschke MW, Merkel D, Scheuer C, Willnecker V, Meyer-Lindenberg A, Menger MD, Naumann A (2010) Perioperative steroid administration inhibits angiogenic host tissue response to porous polyethylene (Medpor) implants. Eur Cell Mater 19:107–116PubMedGoogle Scholar
  30. 30.
    Distler JH, Hirth A, Kurowska-Stolarska M, Gay RE, Gay S, Distler O (2003) Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med 47:149–161PubMedGoogle Scholar
  31. 31.
    Greenberg JI, Cheresh DA (2009) VEGF as an inhibitor of tumor vessel maturation: implications for cancer therapy. Expert Opin Biol Ther 9:1347–1356PubMedCrossRefGoogle Scholar
  32. 32.
    Alvarez RH, Valero V, Hortobagyi GN (2010) Emerging targeted therapies for breast cancer. J Clin Oncol 28:3366–3379PubMedCrossRefGoogle Scholar
  33. 33.
    Cook KM, Figg WD (2010) Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin 60:222–243PubMedCrossRefGoogle Scholar
  34. 34.
    Chegini N, Rossi MJ, Masterson BJ (1992) Platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and EGF and PDGF beta-receptors in human endometrial tissue: localisation and in vitro action. Endocrinology 130:2373–2385PubMedCrossRefGoogle Scholar
  35. 35.
    Moller B, Rasmussen C, Lindblom B, Olovsson M (2001) Expression of the angiogenic growth factors VEGF, FGF-2 m EGF and their receptors in normal human endometrium during the menstrual cycle. Mol Hum Reprod 7:65–72PubMedCrossRefGoogle Scholar
  36. 36.
    Kzhyshkowska J, Gratchev A, Goerdt S (2006) Stabilin-1, a homeostatic scavenger receptor with multiple functions. J Cell Mol Med 10:635–649PubMedCrossRefGoogle Scholar
  37. 37.
    Karikoski M, Irjala H, Maksimow M, Miiluniemi M, Granfors K, Hernesniemi S, Elima K, Moldenhauer G, Schledzewski K, Kzhyshkowska J, Goerdt S, Salmi M, Jalkanen S (2009) Clever-1/Stabilin-1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation. Eur J Immunol 39:3477–3487PubMedCrossRefGoogle Scholar
  38. 38.
    Cupurdija K, Azzola D, Hainz U, Gratchev A, Heitger A, Takikawa O, Goerdt S, Wintersteiger R, Dohr G, Sedlmayr P (2004) Macrophages of human first trimester decidua express markers associated to alternative activation. Am J Reprod Immunol 51:117–122PubMedCrossRefGoogle Scholar
  39. 39.
    Kzhyshkowska J, Workman G, Cardó-Vila M, Arap W, Pasqualini R, Gratchev A, Krusell L, Goerdt S, Sage EH (2006) Novel function of alternatively activated macrophages: stabilin-1-mediated clearance of SPARC. J Immunol 176:5825–5832PubMedGoogle Scholar
  40. 40.
    Chlenski A, Liu S, Crawford SE, Volpert OV, DeVries GH, Evangelista A, Yang Q, Salwen HR, Farrer R, Bray J, Cohn SL (2002) SPARC is a key Schwannian-derived inhibitor controlling neuroblastoma tumor angiogenesis. Cancer Res 62:7357–7363PubMedGoogle Scholar
  41. 41.
    Sage EH, Reed M, Funk SE, Truong T, Steadele M, Puolakkainen P, Maurice DH, Bassuk JA (2003) Cleavage of the matricellular protein SPARC by matrix metalloproteinase 3 produces polypeptides that influence angiogenesis. J Biol Chem 278:37849–37857PubMedCrossRefGoogle Scholar
  42. 42.
    Barker TH, Baneyx G, Cardó-Vila M, Workman GA, Weaver M, Menon PM, Dedhar S, Rempel SA, Arap W, Pasqualini R, Vogel V, Sage EH (2005) SPARC regulates extracellular matrix organization through its modulation of integrin-linked kinase activity. J Biol Chem 280:36483–36493PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Gendie E. Lash
    • 1
  • Judith N. Bulmer
    • 1
  • Barbara A. Innes
    • 1
  • Josephine A. Drury
    • 2
  • Stephen C. Robson
    • 1
  • Siobhan Quenby
    • 3
  1. 1.Reproductive and Vascular Biology Group, Institute of Cellular MedicineNewcastle UniversityNewcastle upon TyneUK
  2. 2.Department of Women’s and Children’s HealthUniversity of LiverpoolLiverpoolUK
  3. 3.Clinical Sciences Research InstituteUniversity of WarwickWarwickUK

Personalised recommendations