Assessment of heparanase and heparin-binding growth and angiogenesis factors in the uterine cavity fluid in women with impaired reproduction

Przemysław Wirstlein; Mateusz Mikołajczyk; Jana Skrzypczak

doi:10.20883/medical.e83

Authors

Przemysław Wirstlein Division of Reproduction, Department of Gynecology and Obstetrics, Poznan University of Medical Sciences, Poland
Mateusz Mikołajczyk Division of Reproduction, Department of Gynecology and Obstetrics, Poznan University of Medical Sciences, Poland
Jana Skrzypczak Division of Reproduction, Department of Gynecology and Obstetrics, Poznan University of Medical Sciences, Poland

DOI:

https://doi.org/10.20883/medical.e83

Keywords:

heparanase, HPA1, heparin binding growth factors, HB-EGF, VEGF, FBF2, recurrent miscarriage, infertility, uterine fluid

Abstract

Introduction. Numerous reports lead to conclusion that either the absence or insufficient amounts of heparanase and heparin binding growth factors on the luminal surface of the epithelium in the endometrium may be associated with impaired reproduction. The aim of this study was to assess the suitability of the fluid from the uterus to predict reproductive disorders.
Material and methods. The group consisted of 32 women with 2 or more consecutive unexplained miscarriages, and 33 idiopathic infertility patients; the control group comprised 22 women with normal reproductive potential. Concentration of the studied factors was assayed by ELISA in uterine fluid.
Results. The uterine flushings from women with two or more consecutive miscarriages showed significantly lower concentrations of HPA1 (p < 0.001) compared to the control group and infertile patients. In contrast, we didn't observe statistically significant differences of concentration of HB-EGF, VEGF, FGF2 in the studied groups. Statistically significant correlations were obtained between the levels of HPA1 and growth factors in all groups p < 0.05. The ROC curve was used to test the diagnostic value of HPA1. With a cut-off point of 8.56 U/L for HPA1 levels, we achieved 58.6% sensitivity and 84.6% specificity in the detection of women with recurrent miscarriage compared to fertile controls and infertile women combined. The area under curve (AUC) value was 0.751.
Conclusions. The procedure for determining the concentrations of HPA1, HB-EGF, VEGF, FGF2 by ELISA in fluids derived from the uterine cavity is insufficient to predict either success of reproduction or reproductive disorders.

Downloads

Download data is not yet available.

References

Gaide Chevronnay HP, Selvais C, Emonard H, Galant C, Marbaix E, Henriet P. Regulation of matrix metalloprotein-ases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration. Biochim Biophys Acta. 2012 Jan;1824(1):146–156.

Dziadek M, Fujiwara S, Paulsson M, Timpl R. Immunological characterization of basement membrane types of heparin sulfate proteoglycan. The EMBO J. 1985 Apr;4(4):905–912.

Kirn-Safran C, D’Souza S, Carson D. Heparan Sulfate Proteoglycans and Their Binding Proteins in Embryo Implantation and Placentation. Semin Cell Dev Biol. 2008 Apr;19(2):187–193.

Ashikada-Hada S, Habuchi H, Kariya Y, Itoh N, Reddi AH, Kimata K. Charakterization of growth factor-binding structures in heparin/heparin sulfate using an octasaccharide library. J Biol Chem. 2004 Mar;279(13): 12346–12354.

MahalingamY, Gallagher JT, Couchman JR. Cellular adhesion responses to the heparin-binding (HepII) domainof fibronectin reqire heparin sulfate with specific properties. J Biol Chem. 2007 Feb 2;282(5):3221–3230.

Bame KJ. Heparanases: endoglycosidases that degrade heparan sulfate proteoglycans. Glycobiology. 2001 Jun;11(6):91R–98R.

Zetser A, Bashenko Y, Edovitsky E, Levy-Adam F, Vlodavsky I, Ilan N. Heparanase induces vascular endothelial growth factor expression: correlation with p38 phosphorylation levels and Src activation. Cancer Res. 2006 Feb 1;66(3):1455–1463.

Vlodavsky I, Ilan N, Nadir Y, Brenner B, Katz BZ, Naggi A, et al. Heparanase, heparin and the coagulation system in cancer progression. Thromb Res. 2007;120(Suppl 2):S112–112.

Elkin M, Ilan N, Ishai-Michaeli R, Friedmann Y, Papo O, Pecker I, et al. Heparanase as mediator of angiogenesis: mode of action. FASEB J. 2001 Jul;15(9):1661–1663.

Goshen R, et al. Purification andcharacterization of placental heparanase and its expression by cultured cytotrophoblasts. Mol Hum Reprod. 1996 Sep;2(9):679–684.

Dempsey LA, Plummer TB, Coombes SL, Platt JL. Heparanase expression in invasive trophoblasts and acute vascular damage. Glycobiology. 2000 May;10(5):467–475.

Kizaki K, Nakano H, Takahashi T, Imai K, Hashizume K. Expression of heparanase mRNA in bovine placenta during gestation. Reproduction. 2001 Apr;121(4):573–580.

Raab G, Kover K, Paria BC, Dey SK, Ezzell RM, Klagsbrun M. Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor. Development. 1996 Feb;122(2):637–645.

Paria BC, Elenius K, Klagsbrun M, Dey SK. Heparin-binding EGF-like growth factor interacts with mouse blastocysts independently of ErbB1: a possible role for heparan sulfate proteoglycans and ErbB4 in blastocyst implantation. Development. 1999 May;126(9):1997–2005.

Schwenke M, Knöfler M, Velicky P, Weimar CH, Kruse M, Samalecos A, et al. Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors. PloS One. 2013;8(1):e54336. DOI: 10.1371/journal.Pone. 0054336

Paiva P, Hannan NJ, Hincks C, Meehan KL, Pruysers E, Dimitriadis E, et al. Human chorionic gonadotrophin regulates FGF2 and other cytokines produced by human endometrial epithelial cells, providing a mechanism for enhancing endometrial receptivity. Hum Reprod. 2011 May;26(5):1153–1162.

Michael DD, Alvarez IM, Ocón OM, Powell AM, Talbot NC, Johnson SE, et al. Fibroblast growth factor-2 is expressed by the bovine uterus and stimulates interferon-tau production in bovine trophectoderm. Endocrinology. 2006 Jul;147(7):3571–3579.

Sugino N, Kashida S, Karube-Harada A, Takiguchi S, Kato H. Expression of vascular endothelial growth factor (VEGF) and its receptors in human endometrium throughout the menstrual cycle and in early pregnancy. Reproduction. 2002 Mar;123(3):379–387.

Boomsma CM, Kavelaars A, Eijkemans MJ, Fauser BC, Heijnen CJ, Macklon NS. Ovarian stimulation for in vitro fertilization alters the intrauterine cytokine, chemokine, and growth factor milieu encountered by the embryo. Fertil Steril. 2010 Oct;94(5):1764–1768.

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 Jan;27(1):183–195.

Metz CE. Basic principles of ROC analysis. Semin Nucl Med. 1978 Oct;8(4):283–298.

Hannan NJ, Paiva P, Meehan KL, Rombauts LJ, Gardner DK, Salamonsen LA. Analysis of fertility-related soluble mediators in human uterine fluid identifies VEGF as a key regulator of embryo implantation. Endocrinology. 2011 Dec;152(12):4948–4956.

Hamilton JA, Iles RK, Gunn LK, Wilson CM, Lower AM, Chard T, Grudzinskas JG. Concentration of placental protein 14 in uterine fl ushings from infertile women: validation of collection technique and method of expression of results. Hum Reprod. 1998 Dec;13(12): 3357–3362.

Mikołajczyk M, Skrzypczak J, Szymanowski K, Wirstlein P. The assessment of LIF in uterine flushing a possible new diagnostic tool in states of impaired fertility. Reprod Biol. 2003 Nov;3(3):259–270.

Ledee-Bateille N, Lapree-Delage G, Taupin JL, Dubanchet S, Frydman R, Chaouat G. Concentration of leukemia inhibitory factor (LIF) in uterine fl ushing fl uid is highly predictive of embryo implantation. Hum Reprod. 2002 Jan;17(1):213–218.

Inagaki N, Stern C, McBain J, Lopata A, Kornman L, Wilkinson D. Analysis of intra-uterine cytokine concentration and matrix-metalloproteinase activity in women with recurrent failed embryo transfer. Hum Reprod. 2003 Mar;18(3):608–615.

Licht P, Lösch A, Dittrich R, Neuwinger J, Siebzehnrübl E, Wildt L. Novel insights into human endometrial paracrinology and embryo-maternal communication by intrauterine microdialysis. Hum Reprod Update. 1998 Sept-Oct;4(5):532–538.

Yoshii N, Hamatani T, Inagaki N, Hosaka T, Inoue O, Yamada M, et al. Successful implantation after reducing matrix metalloproteinase activity in the uterine cavity. Reprod Biol Endocrinol. 2013 May11;11:37. DOI: 10.1186/1477–7827–11–37

Harris LK, Baker PN, Brenchley PE, Aplin JD. Trophoblast-derived heparanase is not required for invasion. Placenta. 2008 Apr;29(4):332–337.

Toyoshima M, Nakajima M. Human heparanase. Purification, characterization, cloning, and expression. J Biol Chem. 1999 Aug 20;274(34):24153–24160.

Gilat D, Hershkoviz R, Goldkorn I, Cahalon L, Korner G, Vlodavsky I, et al. Molecular behavior adapts to context: heparanase functions as an extracellular matrix-degrading enzyme or as a T cell adhesion molecule, depending on the local pH. J Exp Med. 1995 May 1;181(5):1929–1934.

Revel A, Helman A, Koler M, Shushan A, Goldshmidt O, Zcharia E, et al. Heparanase improves mouse embryo implantation. Fertil Steril. 2005 Mar;83(3):580–586.

Wang N, Geng L, Zhang S, He B, Wang J. Expression of PRB, FKBP52 and HB-EGF relating with ultrasonic evaluation of endometrial receptivity. 2012;7(3):e34010. DOI: 10.1371/journal.pone.0034010

Yoo HJ, Barlow DH, Mardon HJ. Temporal and spatial regulation of expression of heparin-binding epidermal growth factor-like growth factor in the human endometrium: a possible role in blastocyst implantation. Dev Genet. 1997;21(1):102–108.

Lessey BA, Gui Y, Apparao KB, Young SL, Mulholland J. Regulated expression of heparin-binding EGF-like growth factor (HB-EGF) in the human endometrium: a potential paracrine role during implantation. Mol Reprod Dev. 2002 Aug;62(4):446–455.

Stavreus-Evers A, Aghajanova L, Brismar H, Eriksson H, Landgren BM, Hovatta O. Co-existence of heparin-binding epidermal growth factor-like growth factor and pinopodes in human endometrium at the time of implantation. Mol Hum Reprod. 2002 Aug;8(8):765–769.

Zhang J, Li Wang, Liquan Cai, Yujing Cao, Enkui Duan. The expression and function of VEGF at embryo implantation “window” in the mouse. Chinese Science Bulletin. 2001 Mar;46(5):409–411.

Möller B, Rasmussen C, Lindblom B, Olovsson M. Expression of the angiogenic growth factors VEGF, FGF-2, EGF and their receptors in normal human endometrium during the menstrual cycle. Mol Hum Reprod. 2001 Jan;7(1):65–72.

Seo WS, Jee BC, Moon SY. Expression of endometrial protein markers in infertile women and the association with subsequent in vitro fertilization outcome. Fertil Steril. 2011 Jun 30;95(8):2707–2710.

Zimmermann G, Ackermann W, Alexander H. Epithelial human chorionic gonadotropin is expressed and produced in human secretory endometrium during the normal menstrual cycle. Biol Reprod. 2009 May;80(5):1053–1065.

Zimmermann G, Ackermann W, Alexander H. Expression and production of human chorionic gonadotropin (hCG) in the normal secretory endometrium: evidence of CGB7 and/or CGB6 beta hCG subunit gene expression. Biol Reprod. 2012 Mar;86(3):87.

Gentilini D, Busacca M, Di Francesco S, Vignali M, Vigano P, Di Blasio AM. PI3K/Akt and ERK1/2 signalling pathways are involved in endometrial cell migration induced by 17beta-estradiol and growth factors. Mol Hum Reprod. 2007 May;13(5):317–322.

Thorsteinsdottir S. Basement membrane and fibronectin matrix are distinct entities in the developing mouse blastocyst. Anat Rec. 1992 Jan;232(1):141–149.

Shimomura Y, Ando H, Furugori K, Kajiyama H, Suzuki M, Iwase A,et al. Possible involvement of crosstalk cell-adhesion mechanism by endometrial CD26/dipeptidyl peptidase IV and embryonal fibronectin in human blastocyst implantation. Mol Hum Reprod. 2006 Aug;12(8):491–495.

Wirstlein PK, Mikołajczyk M, Skrzypczak J. Correlation of the expression of heparanase and heparin-binding EGF-like growth factor in the implantation window of nonconceptual cycle endometrium. Folia Histochem Cytobiol. 2013;51(2):127–134.