Skip to main content

Advertisement

SpringerLink
Log in

Evaluation of extracellular matrix protein expression and apoptosis in the uterosacral ligaments of patients with or without pelvic organ prolapse

  • Original Article
  • Published:
International Urogynecology Journal Aims and scope Submit manuscript

Abstract

Introduction and hypothesis

This study aimed to compare the expression levels of extracellular matrix (ECM) and apoptosis proteins in the uterosacral ligament (USL) of patients with and without pelvic organ prolapse (POP).

Methods

The USL were obtained from patients with POP-Q ≥ III (n = 35) and without POP (n = 20). Immunohistochemistry (IHC) staining and RT-qPCR were conducted to assess the protein and mRNA levels, respectively. The levels of type I collagen (COLI), type III collagen (COLIII), matrix metalloproteinase (MMP)1, MMP2, MMP9, tissue inhibitor of metalloproteinase (TIMP)1, TIMP2, estrogen receptor (ER)α, ERβ and apoptosis-related gene B cell lymphoma 2 (Bcl-2)-associated agonist of cell death (Bad) and Bcl-2-associated X (Bax) in the USL were analyzed.

Results

The protein expression and mRNA levels of MMP2 and MMP9, mRNA levels of BAD and BAX, and protein expression of active cleaved-Caspase3 were significantly higher in the POP group. There were no evident differences in COLIII, MMP1 or ERβ expression at either the mRNA or protein level or in TIMP1, TIMP2 or Caspase3 by IHC between the two groups. However, obvious decreases in COLI and ERα were evident at both the mRNA and protein levels in the POP group, and the mRNA levels of TIMP1 and TIMP2 were also decreased compared to those of the control group.

Conclusion

ECM in the USL tissues of POP patients is remodeled compared with non-POP patients and is characterized by decreased synthesis and increased degradation of collagen; moreover, the levels of the main proteins involved in apoptosis are increased in POP tissue.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Alarab M, Kufaishi H, Lye S, Drutz H, Shynlova O. Expression of extracellular matrix-remodeling proteins is altered in vaginal tissue of premenopausal women with severe pelvic organ prolapse. Reprod Sci. 2014;21(6):704–15. https://doi.org/10.1177/1933719113512529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Smith FJ, Holman CD, Moorin RE, Tsokos N. Lifetime risk of undergoing surgery for pelvic organ prolapse. Obstet Gynecol. 2010;116(5):1096–100. https://doi.org/10.1097/AOG.0b013e3181f73729.

    Article  PubMed  Google Scholar 

  3. John OLD, Lisa KL, Janis MM, Divya AP, Julie AT. Graphic integration of causal factors of pelvic floor disorders: an integrated life span model. Am J Obstet Gynecol. 2008;199(6):610.e611–5. https://doi.org/10.1016/j.ajog.2008.04.001.

    Article  Google Scholar 

  4. Maldonado PA, Wai CY. Pelvic organ prolapse: new concepts in pelvic floor anatomy. Obstet Gynecol Clin N Am. 2016;43(1):15–26. https://doi.org/10.1016/j.ogc.2015.10.001.

    Article  Google Scholar 

  5. Kim T, Sridharan I, Ma Y, Zhu BF, Chi NW, Kobak W, et al. Identifying distinct nanoscopic features of native collagen fibrils towards early diagnosis of pelvic organ prolapse. Nanomed. 2016;12(3):667–75. https://doi.org/10.1016/j.nano.2015.11.006.

    Article  CAS  Google Scholar 

  6. Kerkhof MH, Hendriks L, Brolmann HAM. Changes in connective tissue in patients with pelvic organ prolapse-a review of the current literature. Int Urogynecol J. 2009;20(4):461–74. https://doi.org/10.1007/s00192-008-0737-1.

    Article  CAS  Google Scholar 

  7. Jackson S, James M, Abrams P. The effect of oestradiol on vaginal collagen metabolism in postmenopausal women with genuine stress incontinence. BJOG-Int J Obstet Gy. 2002;109(3):339–44. https://doi.org/10.1111/j.1471-0528.2002.01052.x.

    Article  CAS  Google Scholar 

  8. Li HJ, Haque Z, Lu Q, Li L, Karas R, Mendelsohn M. Steroid receptor coactivator 3 is a coactivator for myocardin, the regulator of smooth muscle transcription and differentiation. Proc Natl Acad Sci U S A. 2007;104:4065–70. https://doi.org/10.1073/pnas.0611639104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Han LY, Wang L, Wang Q, Li HL, Zang H. Association between pelvic organ prolapse and stress urinary incontinence with collagen. Exp Ther Med. 2014;7(5):1337–41. https://doi.org/10.3892/etm.2014.1563.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Zhou L, Lee JH, Wen Y, Constantinou C, Yoshinobu M, Omata S, et al. Biomechanical properties and associated collagen composition in vaginal tissue of women with pelvic organ prolapse. J Urology. 2012;188(3):875–80. https://doi.org/10.1016/j.juro.2012.05.017.

    Article  Google Scholar 

  11. Michal D, Elad L, Jacob D, Moshe M, Ruthy SL. Increased matrix metalloproteinases-1,-9 in the uterosacral ligaments and vaginal tissue from women with pelvic organ prolapse. Eur J Obstet Gyn R B. 2011;156(1):113–7. https://doi.org/10.1016/j.ejogrb.2010.12.043.

    Article  CAS  Google Scholar 

  12. Phillips CH, Anthony F, Benyon C, Monga AK. Collagen metabolism in the uterosacral ligaments and vaginal skin of women with uterine prolapse. BJOG-Int J Obstet Gy. 2006;113(1):39–46. https://doi.org/10.1111/j.1471-0528.2005.00773.x.

    Article  CAS  Google Scholar 

  13. Lang JH, Zhu L, Sun ZJ, Chen J. Estrogen levels and estrogen receptors in patients with stress urinary incontinence and pelvic organ prolapse. Int J Gynaecol Obstet. 2003;80(1):35–9. https://doi.org/10.1016/s0020-7292(02)00232-1.

    Article  CAS  PubMed  Google Scholar 

  14. Ewies AA, Thompson J, Al-Azzawi F. Changes in gonadal steroid receptors in the cardinal ligaments of prolapsed uteri: immunohistomorphometric data. Hum Reprod. 2004;19(7):1622–8. https://doi.org/10.1093/humrep/deh282.

    Article  CAS  PubMed  Google Scholar 

  15. Kim EJ, Chung N, Park SH, Lee KH, Kim SW, Kim JY, et al. Involvement of oxidative stress and mitochondrial apoptosis in the pathogenesis of pelvic organ prolapse. J Urology. 2013;189(2):588–94. https://doi.org/10.1016/j.juro.2012.09.041.

    Article  CAS  Google Scholar 

  16. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495–516. https://doi.org/10.1080/01926230701320337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jackson SR, Avery NC, Tatlton JF, Eckford SD, Abrams P, Bailey AJ. Changes in metabolism of collagen in genitourinary prolapse. Lancet. 1996;347(9016):1658–61. https://doi.org/10.1016/s0140-6736(96)91489-0.

    Article  CAS  PubMed  Google Scholar 

  18. Zeng CY, Liu J, Wang HL, Zhou Y, Wu JW, Yan GR. Correlation between autophagy and collagen deposition in patients with pelvic organ prolapse. Female Pelvic Med Re. 2018;24(3):213–21. https://doi.org/10.1097/Spv.0000000000000455.

    Article  Google Scholar 

  19. Yucel N, Usta A, Guzin K, Kanter M, Bilgic E, Ozel NO, et al. Immunohistochemical analysis of connective tissue in patients with pelvic organ prolapse. J Mol Histol. 2013;44(1):97–102. https://doi.org/10.1007/s10735-012-9456-5.

    Article  CAS  PubMed  Google Scholar 

  20. Välimaa H, Savolainen S, Soukka T, Silvoniemi P, Mäkelä S, Kujari H, et al. Estrogen receptor-β is the predominant estrogen receptor subtype in human oral epithelium and salivary glands. J Endocrinol. 2004;180:55–62. https://doi.org/10.1677/joe.0.1800055.

    Article  PubMed  Google Scholar 

  21. McIntush EW, Smith MF. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in ovarian function. Rev Reprod. 1998;3(1):23–30. https://doi.org/10.1530/ror.0.0030023.

    Article  CAS  PubMed  Google Scholar 

  22. Dietrich W, Elenskaia K, Obermayr E, Horvat R, Mayerhofer K, Umek W, et al. Relaxin and gonadal steroid receptors in uterosacral ligaments of women with and without pelvic organ prolapse. Int Urogynecol J. 2012;23:454–500. https://doi.org/10.1007/s00192-011-1615-9.

    Article  Google Scholar 

  23. Ewies AA, Elshafie M, Li J, Stanley A, Thompson J, Styles J, et al. Changes in transcription profile and cytoskeleton morphology in pelvic ligament fibroblasts in response to stretch: the effects of estradiol and levormeloxifene. Mol Hum Reprod. 2008;14(2):127–35. https://doi.org/10.1093/molehr/gam090.

    Article  CAS  PubMed  Google Scholar 

  24. Borazjani A, Kow N, Harris S, Ridgeway B, Damaser MS. Transcriptional regulation of connective tissue metabolism genes in women with pelvic organ prolapse. Female Pelvic Med Reconstr Surg. 2017;23(1):44–52. https://doi.org/10.1097/SPV.0000000000000337.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Vetuschi A, Pompili S, Gallone A, D’Alfonso A, Carbone MG, Carta G, et al. Immunolocalization of advanced glycation end products, mitogen activated protein kinases, and transforming growth factor-beta/Smads in pelvic organ prolapse. J Histochem Cytochem. 2018;66(9):673–86. https://doi.org/10.1369/0022155418772798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li BS, Guo WJ, Hong L, Liu YD, Liu C, Hong SS, et al. Role of mechanical strain-activated PI3K/Akt signaling pathway in pelvic organ prolapse. Mol Med Rep. 2016;14(1):243–53. https://doi.org/10.3892/mmr.2016.5264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The study was supported by The National Natural Science Foundation of China (81671442, 81971366), the Beijing Natural Science Foundation (Z190021) and the Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (CAMS-2017-I2M-1-002).

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China

    Ya-pei Zhu, Tao Guo, Zhi-jing Sun, Lan Zhu & Jing-he Lang

  2. Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

    Ting Xie

Authors
  1. Ya-pei Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ting Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tao Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhi-jing Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing-he Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhi-jing Sun.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to declare.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Supplementary Fig. 1

RT-qPCR analysis of the relative ratio of COLI/COLIII in the USL tissues of patients in the POP group (n = 35) (gray bars) and control group (n = 20) (black bars). The results represent the mean and standard deviation. p < 0.05 indicates a significant difference, and the specific p value is indicated (TIF 126 kb)

High-resolution image. (PNG 125 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, Yp., Xie, T., Guo, T. et al. Evaluation of extracellular matrix protein expression and apoptosis in the uterosacral ligaments of patients with or without pelvic organ prolapse. Int Urogynecol J 32, 2273–2281 (2021). https://doi.org/10.1007/s00192-020-04446-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00192-020-04446-7

Keywords

Search

Navigation