Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter

IMPACT FACTOR 2018: 3.638

CiteScore 2018: 2.44

SCImago Journal Rank (SJR) 2018: 1.191
Source Normalized Impact per Paper (SNIP) 2018: 1.205

See all formats and pricing
More options …
Volume 53, Issue 9


Expression of vascular endothelial factor-A, gelatinases (MMP-2, MMP-9) and TIMP-1 in uterine leiomyomas

Porfyrios Korompelis / Christina Piperi / Christos Adamopoulos / Georgia Dalagiorgou / Penelope Korkolopoulou / Athanasia Sepsa / Aris Antsaklis
  • Department of Obstetrics and Gynaecology, ‘Alexandra’ Hospital, University of Athens Medical School, Athens, Greece
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Athanasios G. Papavassiliou
Published Online: 2014-12-03 | DOI: https://doi.org/10.1515/cclm-2014-0798


Background: Leiomyomas growth involves cellular hypertrophy, modulation of mitotic activity and upregulation of extracellular matrix (ECM). Vascular factors and matrix metalloproteinases (MMPs) play a coordinated role during neoplasia and tissue remodeling. The present study investigates the role of angiogenic factor vascular endothelial growth factor (VEGF)-A with the activity of main gelatinases, MMP-2/MMP-9 and their tissue inhibitor TIMP-1 in patients with leiomyomas.

Methods: Peripheral blood of 46 women with uterine leiomyomas was obtained prior hysterectomy to assess VEGF-A, MMP-2, -9, TIMP-1 levels by enzyme-linked immunosorbent assay compared to 39 healthy controls. Protein expression levels of VEGF-A, MMP-2 and MMP-9 were evaluated by western immunoblotting and immunohistochemistry in leiomyomas tissue specimens after hysterectomy. Furthermore, the activity of gelatinases in leiomyoma tissue extracts and control myometrium was evaluated by semi-quantitative zymography.

Results: Circulating levels of VEGF-A, MMP-2 and TIMP-1 were significantly elevated in leiomyoma patients compared to controls (p<0.001, p=0.004, p=0.003, respectively). A positive correlation was found between VEGF-A and MMP-2 (p=0.021) as well as MMP-9 (p=0.001) peripheral levels in the patient’s group. Furthermore, increased VEGF-A protein levels were detected in leiomyoma tissue compared to control myometrium, followed by increased localization of both VEGF-A and MMP-2 in the ECM embedding bundles of smooth muscle cells of leiomyomas. The activity of MMP-2 was significantly higher in leiomyomas than normal myometrium in all investigated tissues.

Conclusions: This study demonstrates a possible coordinated role of VEGF-A and MMP-2 during uterine leiomyomas growth and angiogenesis with potential prognostic significance.

Keywords: matrix metalloproteinase (MMP)-2; MMP-9; TIMP-1; uterine leiomyomas; vascular endothelial growth factor (VEGF)-A


  • 1.

    Miura S, Khan KN, Kitajima M, Hiraki K, Moriyama S, Masuzaki H, et al. Differential infiltration of macrophages and prostaglandin production by different uterine leiomyomas. Hum Reprod 2006;21:2545–54.PubMedCrossrefGoogle Scholar

  • 2.

    Eldar-Geva T, Lowe PJ, MacLachlan V, Rombauts L, Healy DL. Different influence of incongruent follicular development on in vitro fertilization embryo transfer and gamete intra fallopian transfer pregnancy rates. Fertil Steril 1998;70:1039–43.CrossrefGoogle Scholar

  • 3.

    Wilcox LS, Koonin LM, Pokras R, Strauss LT, Xia Z, Peterson HB. Hysterectomy in the United States, 1988–1990. Obstet Gynecol 1994;83:549–55.CrossrefGoogle Scholar

  • 4.

    Whiteman MK, Hillis SD, Jamieson DJ, Morrow B, Podgornik MN, Brett KM, et al. Inpatient hysterectomy surveillance in the United States, 2000–2004. Am J Obstet Gynecol 2008;198:34e1–7.Web of ScienceGoogle Scholar

  • 5.

    Wallach EE. Leiomyomas. In: Wallach EE, Zacur HA, editors. Reproductive medicine and surgery. Mosby: St. Louis (MO), 1994:731–46.Google Scholar

  • 6.

    Stewart EA. Uterine fibroids. Lancet 2001;357:293–8.Google Scholar

  • 7.

    Maruo T, Matsuo H, Samoto T, Shimomura Y, Karachi O, Gao Z, et al. Effects of progesterone on uterine leiomyoma growth and apoptosis. Steroids 2000;65:585–92.PubMedCrossrefGoogle Scholar

  • 8.

    Sozen I, Arici A. Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of the uterine leiomyomata. Fertil Steril 2002;78:1–12.CrossrefPubMedGoogle Scholar

  • 9.

    Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect 2003;111:1037–54.CrossrefPubMedGoogle Scholar

  • 10.

    Lethaby A, Vollenhoven B. Fibroids (uterine myomatosis, leiomyomas). Am Fam Physician 2005;9:1753–6.Google Scholar

  • 11.

    Ghahary A, Murphy LJ. Uterine insulin-like growth factor-I receptors: regulation by estrogen and variation throughout the estrous cycle. Endocrinol 1989;125:597–604.Google Scholar

  • 12.

    Wolańska M, Malkowski A, Romanowicz L, Bańkowski E. Does vascular endothelial growth factor participate in uterine myomyoma growth stimulation? Eur J Obstet Gynecol Reprod Biol 2012;164:93–7.Web of ScienceGoogle Scholar

  • 13.

    Corda S, Samuel JL, Rappaport L. Extracellular matrix and growth factors during heart growth. Heart Fail Rev 2000;5:119–30.CrossrefPubMedGoogle Scholar

  • 14.

    Schuppan D, Ruhl M. Matrix in signal transduction and growth factor modulation. Braz J Med Biol Res 1994;27:2125–41.PubMedGoogle Scholar

  • 15.

    Schonherr E, Hausser HJ. Extracellular matrix and cytokines: a functional unit. Dev Immunol 2000;7:89–101.CrossrefPubMedGoogle Scholar

  • 16.

    Wolańska M, Bańkowski E. An accumulation of insulin-like growth factor I (IGF-I) in human myometrium and uterine leiomyomas in various stages of tumour growth. Eur Cytokine Netw 2004;15:359–63.PubMedGoogle Scholar

  • 17.

    Burroughs KD, Howe SR, Okubo Y, Fuchs-Young R, LeRoith D, Walker CL. Dysregulation of IGF-I signaling in uterine leiomyoma. J Endocrinol 2002;172:83–93.Google Scholar

  • 18.

    Houston KD, Hunter DS, Hodges LC, Walker CH. Uterine leiomyomas: mechanisms of tumorigenesis. Toxicol Pathol 2001;1:100–4.CrossrefGoogle Scholar

  • 19.

    Hyder SM, Huang JC, Nawaz Z, Boettger-Tong H, Makela S, Chiappetta C, et al. Regulation of vascular endothelial growth factor expression by estrogens and progestins. Environ Health Perspect 2000;108:785–90.CrossrefPubMedGoogle Scholar

  • 20.

    Charnock-Jones S, Sharkey AS, Rajput-Williams J, Burch D, Schofield JP, Fountain SA, et al. 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.CrossrefGoogle Scholar

  • 21.

    Houck KA, Ferrara N, Winer J, Cachianes G, Leung DW. The vascular endothelial growth factor family. Identification of a fourth molecular species and characterization of alter- native splicing of RNA. Mol Endocrinol 1991;5:1806–14.CrossrefGoogle Scholar

  • 22.

    Gordon JD, Messiano S, Zaloudek CJ, Jaffe RB. Vascular endothelial growth factor localization in human ovary and fallopian tubes: possible role in reproductive function and ovarian cyst formation. J Clin Endocrinol Metabol 1996;81:353–9.Google Scholar

  • 23.

    Kashida S, Sugino N, Takiguchi S, Karube A, Takayama H, Yamagata Y, et al. Regulation and role of vascular endothelial growth factor in the corpus luteum during mid-pregnancy in rats. Biol Reprod 2001;64:317–23.CrossrefPubMedGoogle Scholar

  • 24.

    Machado DE, Abrao MS, Berardo PT, Takiya CM, Nasciutti LE. Vascular density and distribution of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) are significantly higher in patients with deeply infiltrating endometriosis affecting the rectum. Fertil Steril 2007;90:148–55.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 25.

    Bourlev V, Volkov N, Pavlovitch S, Lets N, Larsson A, Olovsson M. The relationship between microvessel density, proliferative activity and expression of vascular endothelial growth factor-A and its receptors in eutopic endometrium and endometriotic lesions. Reproduction 2006;132:501–9.Google Scholar

  • 26.

    Khan KN, Kitajima M, Hiraki K, Fujishita A, Sekine I, Ishimaru T, et al. Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy. Hum Reprod 2010;25:642–53.Web of ScienceCrossrefPubMedGoogle Scholar

  • 27.

    Gentry CC, Okolo SO, Fong LF, Crow JC, Maclean AB, Perrett CW. Quantification of vascular endothelial growth factor-A in leiomyomas and adjacent myometrium. Clin Sci (Lond) 2001;101:691–5.CrossrefPubMedGoogle Scholar

  • 28.

    Fujita M. Histological and biochemical studies of collagen in human uterine leiomyomas. Hokkaido Igaku Zasshi 1985;60:602–15.Google Scholar

  • 29.

    Mosher DF, Sottile J, Wu C, McDonald JA. Assembly of extracellular matrix. Curr Opin Cell Biol 1992;4:810–8.PubMedCrossrefGoogle Scholar

  • 30.

    Matrisian LM. Matrix metalloproteinases gene expression. Ann NY Acad Sci 1994;732:42–50.Google Scholar

  • 31.

    Woessner JF, Jr. The family of matrix metalloproteinases. Ann NY Acad Sci 1994;732:11–21.Google Scholar

  • 32.

    Piperi C, Papavassiliou AG. Molecular mechanisms regulating matrix metalloproteinases. Curr Top Med Chem 2012;12:1095–112.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 33.

    Overall CM. Regulation of tissue inhibitor of matrix metalloproteinases expression. Ann NY Acad Sci 1994;732:51–64.Google Scholar

  • 34.

    Dou Q, Tranuzzer RW, Wiliams RS, Schultz GS, Chegini N. Differential expression of matrix metalloproteinases and their tissue inhibitors in leiomyomata: a mechanism for gonadotrophin releasing hormone agonist-induced tumor regression. Mol Hum Reprod 1997;3:1005–14.CrossrefPubMedGoogle Scholar

  • 35.

    Wolańska M, Sobolewski K, Bańkowski E, Jaworski S. Matrix metalloproteinases of human leiomyoma in various stages of tumor growth. Gynecol Obstet Invest 2004;58:14–8.PubMedCrossrefGoogle Scholar

  • 36.

    Bodner-Adler B, Bodner K, Kimberger O, Czerwenka K, Leodolter S, Mayerhofer K. Expression of matrix metalloproteinases in patients with uterine smooth muscle tumors: an immunohistochemical analysis of MMP-1 and MMP-2 protein expression in leiomyoma, uterine smooth muscle tumor of uncertain malignant potential, and leiomyosarcoma. J Soc Gynecol Investig 2004;11:182–6.PubMedCrossrefGoogle Scholar

  • 37.

    Shan B, Li W, Yang SY, Li ZR. Estrogen up-regulates MMP2/9 expression in endometrial epithelial cell via VEGF-ERK1/2 pathway. Asian Pac J Trop Med 2013;6:826–30.Google Scholar

  • 38.

    Wolańska M, Sobolewski K, Drożdżewicz M, Bańkowski E. Extracellular matrix components in uterine leiomyoma and their alteration during the tumour growth. Mol Cell Biochem 1998;189:145–52.Google Scholar

  • 39.

    Wolańska M, Bańkowski E. Fibroblast growth factor (FGF) in human myometrium and uterine leiomyomas in various stages of tumour growth. Biochimie 2006;88:141–6.CrossrefPubMedGoogle Scholar

  • 40.

    Wolańska M, Bańkowski E. Transforming growth factor beta and platelet-derived growth factor in human myometrium and in uterine leiomyomas at various stages of tumour growth. Eur J Obstet Gynecol Reprod Biol 2007;130:238–44.Web of ScienceGoogle Scholar

  • 41.

    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 USA 2000;97:10972–7.CrossrefGoogle Scholar

  • 42.

    Kumar-Singh S, Weyler J, Martin MJ, Vermeulen PB, Van Marck E. Angiogenic cytokines in mesothelioma: a study of VEGF, FGF-1 and -2, and TGF beta expression. J Pathol 1999;189:72–8.Google Scholar

  • 43.

    Bogusiewicz M, Stryjecka-Zimmer M, Postawski K, Jakimiuk AJ, Rechberger T. Activity of matrix metalloproteinase-2 and -9 and contents of their tissue inhibitors in uterine leiomyoma and corresponding myometrium. Gynecol Endocrinol 2007;23:541–6.Web of ScienceGoogle Scholar

  • 44.

    Moiseva EP. Adhesion receptors of vascular smooth muscle cells and their functions. Cardiovasc Res 2001;52:37286.CrossrefGoogle Scholar

  • 45.

    Fowleks JL, Enghild JJ, Suzuki K, Nagase H. Matrix metalloproteinase degrade insulin-like growth factor binding ptotein-3 in dermal fibroblast cultures. J Biol Chem 1994;269:25742–6.Google Scholar

  • 46.

    You Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-b and promotes tumor invasion and angoigenesis. Genes Dev 2000;14:163–76.Google Scholar

  • 47.

    Wingrove CS, Garr E, Godsland IF, Stevenson JC. 17b-Estradiol enhances release of matrix metalloproteinase-2 from human vascular smooth cells. Biochim Biophysis Acta 1998;1406: 169–74.Google Scholar

  • 48.

    Hulboy DL, Rudolph LA, Matrisian LM. Matrix metalloproteinases as mediators of reproductive function. Mol Hum Reprod 1997;3:27–45.CrossrefPubMedGoogle Scholar

  • 49.

    Bergers G. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol 2000;2:737–44.CrossrefGoogle Scholar

About the article

Corresponding author: Christina Piperi, Department of Biological Chemistry, University of Athens Medical School, 75 M. Asias Street, 11527 Athens, Greece, Phone: +30 210 7462610, Fax: +30 210 7791207, E-mail:

aChristina Piperi and Christos Adamopoulos contributed equally to this work.

Received: 2014-08-05

Accepted: 2014-10-27

Published Online: 2014-12-03

Published in Print: 2015-08-01

Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 53, Issue 9, Pages 1415–1424, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2014-0798.

Export Citation

©2015 by De Gruyter.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Bruna de Almeida, Natalia Garcia, Giovana Maffazioli, Laura Gonzalez dos Anjos, Edmund Chada Baracat, and Katia Candido Carvalho
International Journal of Molecular Sciences, 2017, Volume 19, Number 1, Page 52
Jeris Cox, Minnie Malik, Joy Britten, Terrence Lewis, and William H. Catherino
Reproductive Sciences, 2017, Page 193371911772880
Marwa Kamel, Mohamed Wagih, Gokhan S. Kilic, Concepcion R. Diaz-Arrastia, Mohamed A. Baraka, and Salama A. Salama
BioMed Research International, 2017, Volume 2017, Page 1
Ricardo Bassil Lasmar and Bernardo Portugal Lasmar
Best Practice & Research Clinical Obstetrics & Gynaecology, 2017, Volume 40, Page 82

Comments (0)

Please log in or register to comment.
Log in