Skip to main content

Advertisement

SpringerLink
Log in

Prevention of intrauterine fetal growth restriction by administrating C1q/TNF-related protein 6, a specific inhibitor of the alternative complement pathway

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

The latest treatments do not sufficiently prevent miscarriage and fetal growth restriction (FGR) in pregnant women. Here, we assessed the effects of a human protein, CTRP6, that specifically inhibits the activation of the alternative complement pathway on miscarriage, fetal and placental development.

Methods

Pregnant CBA/J mice mated with DBA/2 male mice as a model of spontaneous abortion and FGR were randomly divided into the control and CTRP6 groups. In the CTRP6 group, the mice were intravenously administered CTRP6 on days 4.5 and 6.5 post-conception (dpc). The abortion rate and fetal and placental weights on 14.5 dpc were examined. Remodeling of the spiral artery was also assessed.

Results

The abortion rate in the CTRP6 group (13%) was reduced compared to the control group (21%), but there was no statistical difference. The placental and fetal weights in the CTRP6 group were also heavier than those in the control (P < 0.05). Moreover, the thickness of the blood vessel wall in the CTRP6 group was significantly thinner than that in the control (P < 0.05) and comparable to that in the non-abortion model (CBA/J x BALB). The ratio of the inner-per-the-outer diameter of the spiral artery increased more in the CTRP6 group than that in the control (P < 0.05). As well, the Th1/Th2 cytokine ratio was significantly reduced by CTRP6 treatment.

Conclusions

Taken together, the supplementation with a protein that regulates the alternative complement pathway in vivo improves FGR and promotes spiral artery remodeling in a mouse model of miscarriage and FGR.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Sugiura-Ogasawara M, Ozaki Y, Katano K, Suzumori N, Kitaori T, Mizutani E. Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage. Hum Reprod. 2012;27:2297–303.

    Article  PubMed  Google Scholar 

  2. Munné S, Kaplan B, Frattarelli JL, Child T, Nakhuda G, Shamma FN, Silverberg K, Kalista T, Handyside AH, Katz-Jaffe M, Wells D, Gordon T, Stock-Myer S, Willman S, STAR Study Group. Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: a multicenter randomized clinical trial. Fertil Steril. 2019;112:1071–9.

    Article  PubMed  CAS  Google Scholar 

  3. Sato T, Sugiura-Ogasawara M, Ozawa F, Yamamoto T, Kato T, Kurahashi H, Kuroda T, Aoyama N, Kato K, Kobayashi R, Fukuda A, Utsunomiya T, Kuwahara A, Saito H, Takeshita T, Irahara M. Preimplantation genetic testing for aneuploidy: a comparison of live birth rates in patients with recurrent pregnancy loss due to embryonic aneuploidy or recurrent implantation failure. Hum Reprod. 2019;34:2340–428.

    Article  PubMed  Google Scholar 

  4. Le Bouteiller P, Bensussan A. Up-and-down immunity of pregnancy in humans. F1000Res. 2017;6:1216.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R. A class I antigen, HLA-G, expressed in human trophoblasts. Science. 1990;248:220–3.

    Article  CAS  PubMed  Google Scholar 

  6. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191–3.

    Article  CAS  PubMed  Google Scholar 

  7. Trowsdale J, Betz AG. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nat Immunol. 2006;7:241–6.

    Article  CAS  PubMed  Google Scholar 

  8. Moffett A, Colucci F. Uterine NK-cells: active regulators at the maternal-fetal interface. J Clin Invest. 2014;124:1872–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. El Costa H, Tabiasco J, Berrebi A, Parant O, Aguerre-Girr M, Piccinni MP, Le Bouteiller P. Effector functions of human decidual NK cells in healthy early pregnancy are dependent on the specific engagement of natural cytotoxicity receptors. J Reprod Immunol. 2009;82:142–7.

    Article  PubMed  CAS  Google Scholar 

  10. Yang F, Zheng Q, Jin L. Dynamic function and composition changes of immune cells during normal and pathological pregnancy at the maternal-fetal interface. Front Immunol. 2019;10:2317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang W, Sung N, Gilman-Sachs A, Kwak-Kim J. T Helper (Th) Cell profiles in pregnancy and recurrent pregnancy losses: Th1/Th2/Th9/Th17/Th22/Tfh cells. Front Immunol. 2020;11:2025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lin Y, Ren L, Wang W, Di J, Zeng S, Saito S. Effect of TLR3 and TLR7 activation in uterine NK cells from non-obese diabetic (NOD) mice. J Reprod Immunol. 2009;82:12–3.

    Article  CAS  PubMed  Google Scholar 

  13. Girardi G, Yarilin D, Thurman JM, Holers VM, Salmon JE. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med. 2006;203:2165–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Goldman AS, Prabhakar BS. The complement system. in: Baron’s Medical Microbiology (Baron S et al, eds.) (4th ed. ed.). Univ of Texas Medical Branch. 1996

  15. Girardi G, Prohászka Z, Bulla R, Tedesco F, Scherjon S. Complement activation in animal and human pregnancies as a model for immunological recognition. Mol Immunol. 2011;48:1621–30.

    Article  CAS  PubMed  Google Scholar 

  16. van de Geijn FE, Dolhain RJ, van Rijs W, Hazes JM, de Groot CJ. Mannose-binding lectin genotypes and pre-eclampsia: a case-control study. Hum Immunol. 2007;68:888–93.

    Article  PubMed  CAS  Google Scholar 

  17. Than NG, Romero R, Erez O, Kusanovic JP, Tarca AL, Edwin SS, Kim JS, Hassan SS, Espinoza J, Mittal P, Mazaki-Tovi S, Friel L, Gotsch F, Vaisbuch E, Camacho N, Papp Z. A role for mannose-binding lectin, a component of the innate immune system in pre-eclampsia. Am J Reprod Immunol. 2008;60:333–45.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Vianna P, Da Silva GK, Dos Santos BP, Bauer ME, Dalmáz CA, Bandinelli E, Chies JA. Association between mannose-binding lectin gene polymorphisms and pre-eclampsia in Brazilian women. Am J Reprod Immunol. 2010;64:359–74.

    CAS  PubMed  Google Scholar 

  19. Glotov AS, Tiys ES, Vashukova ES, Pakin VS, Demenkov PS, Saik OV, Ivanisenko TV, Arzhanova ON, Mozgovaya EV, Zainulina MS, Kolchanov NA, Baranov VS, Ivanisenko VA. Molecular association of pathogenetic contributors to pre-eclampsia (pre-eclampsia associome). BMC Syst Biol. 2015;9:S4.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wu W, Yang H, Feng Y, Zhang P, Li S, Wang X, Peng T, Wang F, Xie B, Guo P, Li M, Wang Y, Zhao N, Wang D, Wang S, Zhang Y. Polymorphisms in complement genes and risk of preeclampsia in Taiyuan. China Inflamm Res. 2016;65:837–45.

    Article  CAS  PubMed  Google Scholar 

  21. Poveda NE, Garcés MF, Ruiz-Linares CE, Varón D, Valderrama S, Sanchez E, Castiblanco-Cortes A, Agudelo-Zapata Y, Sandoval-Alzate HF, Leal LG, Ángel-Müller E, Ruíz-Parra AI, González-Clavijo AM, Diéguez C, Nogueiras R, Caminos JE. Serum adipsin levels throughout normal pregnancy and preeclampsia. Sci Rep. 2016;6:20073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wong GW, Krawczyk SA, Kitidis-Mitrokostas C, Revett T, Gimeno R, Lodish HF. Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions. Biochem J. 2008;416:161–77.

    Article  CAS  PubMed  Google Scholar 

  23. Murayama MA, Kakuta S, Inoue A, Umeda N, Yonezawa T, Maruhashi T, Tateishi K, Ishigame H, Yabe R, Ikeda S, Seno A, Chi HH, Hashiguchi Y, Kurata R, Tada T, Kubo S, Sato N, Liu Y, Hattori M, Saijo S, Matsushita M, Fujita T, Sumida T, Iwakura Y. CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis. Nat Commun. 2015;6:8483.

    Article  CAS  PubMed  Google Scholar 

  24. Sadeghi A, Fadaei R, Moradi N, Fouani FZ, Roozbehkia M, Zandieh Z, Ansaripour S, Vatannejad A, Doustimotlagh AH. Circulating levels of C1q/TNF-α-related protein 6 (CTRP6) in polycystic ovary syndrome. IUBMB Life. 2020;72:1449–59.

    Article  CAS  PubMed  Google Scholar 

  25. Tuteja G, Cheng E, Papadakis H, Bejerano G. A comprehensive database of SNPs studied in association with pre-eclampsia. Placenta. 2012;33:1055–7.

    Article  CAS  PubMed  Google Scholar 

  26. Clark DA, Chaouat G, Arck PC, Mittruecker HW, Levy GA. Cytokine-dependent abortion in CBA × DBA/2 mice is mediated by the procoagulant fgl2 prothrombinase [correction of prothombinase]. J Immunol. 1998;160:545–9.

    CAS  PubMed  Google Scholar 

  27. Girardi G. Guilty as charged: all available evidence implicates complement’s role in fetal demise. Am J Reprod Immunol. 2008;59:183–92.

    Article  CAS  PubMed  Google Scholar 

  28. McKelvey K, Yenson V, Ashton A, Morris JM, McCracken SA. Embryonic/fetal mortality and intrauterine growth restriction is not exclusive to the CBA/J sub-strain in the CBA × DBA model. Sci Rep. 2016;6:35138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Takeshita A, Kusakabe KT, Hiyama M, Kuniyoshi N, Kondo T, Kano K, Kiso Y, Okada T. Dynamics and reproductive effects of complement factors in the spontaneous abortion model of CBA/J×DBA/2 mice. Immunobiology. 2014;219:385–91.

    Article  CAS  PubMed  Google Scholar 

  30. Schumacher A, Sharkey DJ, Robertson SA, Zenclussen AC. Immune cells at the fetomaternal interface: how the microenvironment modulates immune cells to hoster fetal development. J Immunol. 2018;201:325–34.

    Article  CAS  PubMed  Google Scholar 

  31. Fraser R, Whitley GS, Johnstone AP, Host AJ, Sebire NJ, Thilaganathan B, Cartwright JE. Impaired decidual natural killer cell regulation of vascular remodelling in early human pregnancies with high uterine artery resistance. J Pathol. 2012;228:322–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Charalambous F, Elia A, Georgiades P. Decidual spiral artery remodeling during early post-implantation period in mice: investigation of associations with decidual uNK cells and invasive trophoblast. Biochem Biophys Res Commun. 2012;417:847–52.

    Article  CAS  PubMed  Google Scholar 

  33. Staff AC. The two-stage placental model of preeclampsia: an update. J Reprod Immunol. 2019;134–5:1–10.

    Article  Google Scholar 

  34. Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: pathophysiology, challenges, and perspectives. Circ Res. 2019;124:1094–112.

    Article  CAS  PubMed  Google Scholar 

  35. Sugiura-Ogasawara M, Nozawa K, Nakanishi T, Hattori Y, Ozaki Y. Complement as a predictor of further miscarriage in couples with recurrent miscarriages. Hum Reprod. 2006;21:2711–4.

    Article  CAS  PubMed  Google Scholar 

  36. Xu C, Mao D, Holers VM, Palanca B, Cheng AM, Molina H. A critical role for murine complement regulator crry in fetomaternal tolerance. Science. 2000;287:498–501.

    Article  CAS  PubMed  Google Scholar 

  37. Cunningham DS, Tichenor JR. Decay-accelerating factor protects human trophoblast from complement-mediated attack. Clin Immunol Immunopathol. 1995;74:156–61.

    Article  CAS  PubMed  Google Scholar 

  38. Girardi G. Complement activation, a threat to pregnancy. Semin Immunopathol. 2018;40:103–11.

    Article  CAS  PubMed  Google Scholar 

  39. Brooks JP, Radojicic C, Riedl MA, Newcomer SD, Banerji A, Hsu FI. Experience with intravenous plasma-derived C1-inhibitor in pregnant women with hereditary angioedema: a systematic literature review. J Allergy Clin Immunol Pract. 2020;8:1875–80.

    Article  PubMed  Google Scholar 

  40. Sarno L, Tufano A, Maruotti GM, Martinelli P, Balletta MM, Russo D. Eculizumab in pregnancy: a narrative overview. J Nephrol. 2019;32:17–25.

    Article  CAS  PubMed  Google Scholar 

  41. Höchsmann B, Murakami Y, Osato M, Knaus A, Kawamoto M, Inoue N, Hirata T, Murata S, Anliker M, Eggermann T, Jäger M, Floettmann R, Höllein A, Murase S, Ueda Y, Nishimura JI, Kanakura Y, Kohara N, Schrezenmeier H, Krawitz PM, Kinoshita T. Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation. J Clin Invest. 2019;129:5123–36.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308:1592–4.

    Article  CAS  PubMed  Google Scholar 

  43. Nakagawa K, Kwak-Kim J, Kuroda K, Sugiyama R, Yamaguchi K. Immunosuppressive treatment using tacrolimus promotes pregnancy outcome in infertile women with repeated implantation failures. Am J Reprod Immunol. 2017 Sep;78(3):e12682.

    Article  CAS  Google Scholar 

  44. Nakagawa K, Kwan-Kim J, Ota K, Kuroda K, Hisano M, Sugiyama R, Yamaguchi K. Immunosuppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood TH1/TH2 cell ratios. Am J Reprod Immunol. 2015;7:353–61.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Brian Nolan for editing a draft of this manuscript.

Funding

Part of this work was supported by grants from the Japan Society for the Promotion of Science (KAKENHI 18H06257 and 19K18649 to AT, and 20K09674 to SH). Histological experiments and ELISA were performed in Research Support Platform of Osaka City University Graduate School of Medicine.

Author information

Authors and Affiliations

  1. Women’s Lifecare Medicine, Obstetrics and Gynecology, School of Medicine, Osaka City University, 545-8585, Osaka, Japan

    Mayu Kurokawa, Masayasu Koyama & Daisuke Tachibana

  2. Graduate School of Medicine, Reproductive Science, Osaka City University, Osaka, 545-8585, Japan

    Mayu Kurokawa, Ai Takeshita & Shu Hashimoto

  3. Department of Anatomy and Neurobiology, Faculty of Medicine, Kindai University, Osaka, 589-8511, Japan

    Ai Takeshita

  4. HORAC Grand Front Osaka Clinic, Osaka, 530-0011, Japan

    Yoshiharu Morimoto

Authors
  1. Mayu Kurokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ai Takeshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shu Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masayasu Koyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshiharu Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daisuke Tachibana
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MK, AT, and SH designed the experiment, interpreted the results, and wrote the manuscript with the help from all authors. MK, YM, and DT supervised the project.

Corresponding author

Correspondence to Shu Hashimoto.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PPTX 49 KB)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kurokawa, M., Takeshita, A., Hashimoto, S. et al. Prevention of intrauterine fetal growth restriction by administrating C1q/TNF-related protein 6, a specific inhibitor of the alternative complement pathway. J Assist Reprod Genet 39, 2191–2199 (2022). https://doi.org/10.1007/s10815-022-02582-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-022-02582-1

Keywords

Search

Navigation