Prevention of Intrauterine Fetal Growth Restriction by Administrating C1q/TNF-related Protein 6, a Specific Inhibitor of the Alternative Complement Pathway

Overview

Journal J Assist Reprod Genet

Publisher Springer

Specialties Genetics
Reproductive Medicine

Date 2022 Jul 30

PMID 35907048

Authors

Mayu Kurokawa

Ai Takeshita

Shu Hashimoto

Masayasu Koyama

Yoshiharu Morimoto

Daisuke Tachibana

Affiliations

Soon will be listed here.

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.

Citing Articles

Localization and expression of C1QTNF6 in chicken follicles and its regulatory effect on follicular granulosa cells.

Li C, Li Q, Wu X, Zhang Z, Li J, Jiang R Poult Sci. 2024; 104(1):104538.

PMID: 39566174 PMC: 11617251. DOI: 10.1016/j.psj.2024.104538.

Characterizing the Dynamic Expression of C1q/TNF-α-Related Protein 6 (CTRP6) during Pregnancy in Humans and Mice with Gestational Diabetes Mellitus.

Jiang J, Wei S, Chen M, Tan Y, Yang Z, Yang G Biomedicines. 2024; 12(5).

PMID: 38791090 PMC: 11117843. DOI: 10.3390/biomedicines12051128.

References

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(8):2297-303. DOI: 10.1093/humrep/des179. View

Munne S, Kaplan B, Frattarelli J, Child T, Nakhuda G, Shamma F . 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(6):1071-1079.e7. DOI: 10.1016/j.fertnstert.2019.07.1346. View

Sato T, Sugiura-Ogasawara M, Ozawa F, Yamamoto T, Kato T, Kurahashi H . 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(12):2340-2348. DOI: 10.1093/humrep/dez229. View

Le Bouteiller P, Bensussan A . Up-and-down immunity of pregnancy in humans. F1000Res. 2017; 6:1216. PMC: 5531158. DOI: 10.12688/f1000research.11690.1. View

Kovats S, Main E, Librach C, Stubblebine M, Fisher S, Demars R . A class I antigen, HLA-G, expressed in human trophoblasts. Science. 1990; 248(4952):220-3. DOI: 10.1126/science.2326636. View

Munn D, Zhou M, Attwood J, Bondarev I, Conway S, Marshall B . Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998; 281(5380):1191-3. DOI: 10.1126/science.281.5380.1191. View

Trowsdale J, Betz A . Mother's little helpers: mechanisms of maternal-fetal tolerance. Nat Immunol. 2006; 7(3):241-6. DOI: 10.1038/ni1317. View

Moffett A, Colucci F . Uterine NK cells: active regulators at the maternal-fetal interface. J Clin Invest. 2014; 124(5):1872-9. PMC: 4001528. DOI: 10.1172/JCI68107. View

El Costa H, Tabiasco J, Berrebi A, Parant O, Aguerre-Girr M, Piccinni M . 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(2):142-7. DOI: 10.1016/j.jri.2009.06.123. View

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. PMC: 6813251. DOI: 10.3389/fimmu.2019.02317. View

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. PMC: 7461801. DOI: 10.3389/fimmu.2020.02025. View

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(1):12-23. DOI: 10.1016/j.jri.2009.03.004. View

13.

Girardi G, Yarilin D, Thurman J, Holers V, Salmon J . Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med. 2006; 203(9):2165-75. PMC: 2118387. DOI: 10.1084/jem.20061022. View

14.

Girardi G, Prohaszka Z, Bulla R, Tedesco F, Scherjon S . Complement activation in animal and human pregnancies as a model for immunological recognition. Mol Immunol. 2011; 48(14):1621-30. DOI: 10.1016/j.molimm.2011.04.011. View

15.

van de Geijn F, Dolhain R, van Rijs W, Hazes J, de Groot C . Mannose-binding lectin genotypes and pre-eclampsia: a case-control study. Hum Immunol. 2007; 68(11):888-93. DOI: 10.1016/j.humimm.2007.10.002. View

16.

Than N, Romero R, Erez O, Kusanovic J, Tarca A, Edwin S . A role for mannose-binding lectin, a component of the innate immune system in pre-eclampsia. Am J Reprod Immunol. 2008; 60(4):333-45. PMC: 2775464. DOI: 10.1111/j.1600-0897.2008.00631.x. View

17.

Vianna P, Kniphoff da Silva G, Paiva Dos Santos B, Bauer M, Dalmaz C, Bandinelli E . Association between mannose-binding lectin gene polymorphisms and pre-eclampsia in Brazilian women. Am J Reprod Immunol. 2010; 64(5):359-74. DOI: 10.1111/j.1600-0897.2010.00846.x. View

18.

Glotov A, Tiys E, Vashukova E, Pakin V, Demenkov P, Saik O . Molecular association of pathogenetic contributors to pre-eclampsia (pre-eclampsia associome). BMC Syst Biol. 2015; 9 Suppl 2:S4. PMC: 4407242. DOI: 10.1186/1752-0509-9-S2-S4. View

19.

Wu W, Yang H, Feng Y, Zhang P, Li S, Wang X . Polymorphisms in complement genes and risk of preeclampsia in Taiyuan, China. Inflamm Res. 2016; 65(10):837-45. DOI: 10.1007/s00011-016-0968-4. View

20.

Poveda N, Garces M, Ruiz-Linares C, Varon D, Valderrama S, Sanchez E . Serum Adipsin Levels throughout Normal Pregnancy and Preeclampsia. Sci Rep. 2016; 6:20073. PMC: 4735521. DOI: 10.1038/srep20073. View