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H19 regulates angiogenic capacity of extravillous trophoblasts by H19/miR-106a-5p/VEGFA axis

  • Maternal-Fetal Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

To investigate the role and underlying mechanism of H19 in regulating angiogenic capacity of extravillous trophoblasts.

Methods

Gain and loss of function experiments were performed using a human first-trimester extravillous trophoblast (EVT) cell line, HTR-8/SVneo cells. H19 was overexpressed or knocked down in HTR-8 cells by transfecting plasmid harboring whole-length H19 sequence (pH19) or siRNA specially targeting H19, respectively (siH19). Cell migration and tube-formation assay were assessed in the indicated groups. Gene expression was detected by RT-qPCR, Western blot, and ELISA assay.

Results

Overexpression of H19 in EVT cells increased cell migration and tube formation, while downregulation of H19 in EVT cells decreased cell migration and tube formation. Furthermore, we found that H19 played its role by VEGFA. In addition, we demonstrated the H19/miR-106a-5p/VEGFA regulatory axis in EVT. Experiments of the clinical specimen showed that H19 was very abundantly expressed in human first-trimester trophoblasts, and we found that the expression of H19 and VEGFA were significantly downregulated in the villous tissues from idiopathic recurrent miscarriage (RM) patients; moreover, the expression of H19 and VEGFA was positively correlated.

Conclusion

H19/miR-106a-5p/VEGFA axis plays a role in regulating the angiogenic capacity of EVT, which might contribute to idiopathic RM.

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References

  1. He D, Zeng H, Chen J et al (2019) H19 regulates trophoblastic spheroid adhesion by competitively binding to let-7. Reprod 157(5):423–430

    Article  CAS  Google Scholar 

  2. Zuckerwise L, Li J, Lu L et al (2016) H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TbetaR3 in placentae with fetal growth restriction. Oncotarget 7(25):38398–38407

    Article  Google Scholar 

  3. Torry DS, Leavenworth J, Chang M et al (2007) Angiogenesis in implantation. J Assist Reprod Genet 24(7):303–315

    Article  Google Scholar 

  4. Wulff C, Weigand M, Kreienberg R et al (2003) Angiogenesis during primate placentation in health and disease. Reproduction 126(5):569–577

    Article  CAS  Google Scholar 

  5. Bischof P, Irminger-Finger I (2005) The human cytotrophoblastic cell, a mononuclear chameleon. Int J Biochem Cell Biol 37(1):1–16

    Article  CAS  Google Scholar 

  6. Ishii T, Miyazawa M, Takanashi Y et al (2014) Genetically induced oxidative stress in mice causes thrombocytosis, splenomegaly and placental angiodysplasia that leads to recurrent abortion. Redox Biol 2:679–685

    Article  CAS  Google Scholar 

  7. Banerjee P, Ghosh S, Dutta M et al (2013) Identification of key contributory factors responsible for vascular dysfunction in idiopathic recurrent spontaneous miscarriage. PLoS ONE 8(11):e80940

    Article  CAS  Google Scholar 

  8. Zhu Y, Lu H, Huo Z et al (2016) MicroRNA-16 inhibits feto-maternal angiogenesis and causes recurrent spontaneous abortion by targeting vascular endothelial growth factor. Sci Rep 6:35536

    Article  CAS  Google Scholar 

  9. Klauber N, Rohan RM, Flynn E et al (1997) Critical components of the female reproductive pathway are suppressed by the angiogenesis inhibitor AGM-1470. Nat Med 3(4):443–446

    Article  CAS  Google Scholar 

  10. Meegdes BH, Ingenhoes R, Peeters LL et al (1988) Early pregnancy wastage: relationship between chorionic vascularization and embryonic development. Fertil Steril 49(2):216–220

    Article  CAS  Google Scholar 

  11. Zeng H, Fan X, Liu N (2017) Expression of H19 imprinted gene in patients with repeated implantation failure during the window of implantation. Arch Gynecol Obstet 296(4):835–839

    Article  CAS  Google Scholar 

  12. Poirier F, Chan CT, Timmons PM et al (1991) The murine H19 gene is activated during embryonic stem cell differentiation in vitro and at the time of implantation in the developing embryo. Development 113(4):1105–1114

    PubMed  CAS  Google Scholar 

  13. Xu J, Xia Y, Zhang H et al (2018) Overexpression of long non-coding RNA H19 promotes invasion and autophagy via the PI3K/AKT/mTOR pathways in trophoblast cells. Biomed Pharmacother 101:691–697

    Article  CAS  Google Scholar 

  14. Jauniaux E, Poston L, Burton GJ (2006) Placental-related diseases of pregnancy: involvement of oxidative stress and implications in human evolution. Hum Reprod Update 12(6):747–755

    Article  CAS  Google Scholar 

  15. Voellenkle C, Garcia-Manteiga JM, Pedrotti S et al (2016) Implication of long noncoding RNAs in the endothelial cell response to hypoxia revealed by RNA-sequencing. Sci Rep 6(1):24141

    Article  CAS  Google Scholar 

  16. Hou J, Wang L, Wu Q et al (2018) Long noncoding RNA H19 upregulates vascular endothelial growth factor A to enhance mesenchymal stem cells survival and angiogenic capacity by inhibiting miR-199a-5p. Stem Cell Res Ther 9(1):109

    Article  CAS  Google Scholar 

  17. Zhang C, Li Q, Ren N et al (2015) Placental miR-106a~363 cluster is dysregulated in preeclamptic placenta. Placenta 36(2):250–252

    Article  CAS  Google Scholar 

  18. Premlata K, Yanmin L, Carmen T et al (2013) The c-Myc-regulated microRNA-17~92 (miR-17~92) and miR-106a~363 clusters target hCYP19A1 and hGCM1 to inhibit human trophoblast differentiation. Mol Cell Biol 33(9):1782–1796

    Article  CAS  Google Scholar 

  19. Fang Y, Yu S, Ma Y et al (2013) Association of Dll4/notch and HIF-1a-VEGF signaling in the angiogenesis of missed abortion. PLoS ONE 8(8):e70667

    Article  CAS  Google Scholar 

  20. Meher A, Sundrani D, Joshi S (2015) Maternal nutrition influences angiogenesis in the placenta through peroxisome proliferator activated receptors: a novel hypothesis. Mol Reprod Dev 82(10):726–734

    Article  CAS  Google Scholar 

  21. De Falco S (2012) The discovery of placenta growth factor and its biological activity. Exp Mol Med 44(1):1–9

    Article  CAS  Google Scholar 

  22. Hiratsuka S, Kataoka Y, Nakao K et al (2005) Vascular endothelial growth factor A (VEGF-A) is involved in guidance of VEGF receptor-positive cells to the anterior portion of early embryos. Mol Cell Biol 25(1):355–363

    Article  CAS  Google Scholar 

  23. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25(4):581–611

    Article  CAS  Google Scholar 

  24. Amirchaghmaghi E, Rezaei A, Moini A et al (2015) Gene expression analysis of VEGF and its receptors and assessment of its serum level in unexplained recurrent spontaneous abortion. Cell J 16(4):538–545

    PubMed  PubMed Central  Google Scholar 

  25. Kutluer G, Cicek NM, Moraloglu O et al (2012) Low VEGF expression in conceptus material and maternal serum AFP and beta-hCG levels as indicators of defective angiogenesis in first-trimester miscarriages. J Turk Ger Gynecol Assoc 13(2):111–117

    PubMed  PubMed Central  Google Scholar 

  26. Bagheri A, Kumar P, Kamath A et al (2017) Association of angiogenic cytokines (VEGF-A and VEGF-C) and clinical characteristic in women with unexplained recurrent miscarriage. Bratisl Lek Listy 118(5):258–264

    PubMed  CAS  Google Scholar 

  27. Plaisier M, Dennert I, Rost E et al (2009) Decidual vascularization and the expression of angiogenic growth factors and proteases in first trimester spontaneous abortions. Hum Reprod 24(1):185–197

    Article  CAS  Google Scholar 

  28. Vuorela P, Carpen O, Tulppala M et al (2000) VEGF, its receptors and the tie receptors in recurrent miscarriage. Mol Hum Reprod 6(3):276–282

    Article  CAS  Google Scholar 

  29. Almawi WY, Saldanha FL, Mahmood NA et al (2013) Relationship between VEGFA polymorphisms and serum VEGF protein levels and recurrent spontaneous miscarriage. Hum Reprod 28(10):2628–2635

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Nongzhang Chen for her kindly help of collecting villous tissues.

Funding

This study was funded by the National Natural Science Foundation of China (https://www.nsfc.gov.cn/) (Grant number 81571441).

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Authors and Affiliations

  1. Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, China

    Hong Zeng, Dongmei He, Yuhao Zhao, Zhaoqun Peng, Huan Deng & Nenghui Liu

  2. Changsha Central Hospital, Changsha, 410004, China

    Hebin Xie, Zhaoqun Peng, Huan Deng, Jinyue Hu & Binyuan Jiang

Authors
  1. Hong Zeng
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  2. Dongmei He
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  3. Hebin Xie
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  4. Yuhao Zhao
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  5. Zhaoqun Peng
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  6. Huan Deng
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  7. Jinyue Hu
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  8. Binyuan Jiang
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  9. Nenghui Liu
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Contributions

NL was involved in the project designing, project development and manuscript revising. HZ and DH contributed to the project designing, project development, data collection, data analysis and manuscript writing. HX, YZ, JH, and BJ contributed to project development and data analysis.

Corresponding author

Correspondence to Nenghui Liu.

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Conflict of interest

We declare that we have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The project was approved by the ethical committee of Xiangya Hospital.

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Informed consent was obtained from all individual participants included in the study.

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Zeng, H., He, D., Xie, H. et al. H19 regulates angiogenic capacity of extravillous trophoblasts by H19/miR-106a-5p/VEGFA axis. Arch Gynecol Obstet 301, 671–679 (2020). https://doi.org/10.1007/s00404-020-05469-7

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  • DOI: https://doi.org/10.1007/s00404-020-05469-7

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