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The role and mechanism of asymmetric dimethylarginine in fetal growth restriction via interference with endothelial function and angiogenesis

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

Abstract

Purpose

Fetal growth restriction (FGR) is a high-risk pregnancy, and placental dysfunction is the main cause of FGR. The upregulation of asymmetric dimethylarginine (ADMA) is linked to FGR pathology, but the mechanism needs to be investigated.

Methods

The levels of ADMA and other related molecules were measured in human biological samples. We further used human umbilical vein endothelial cells (HUVECs) to reveal the mechanism of ADMA-induced FGR in vitro.

Results

Compared with the control group, FGR patients had higher placental resistance, and ADMA levels were increased in the maternal blood, cord blood, and placenta; additionally, nitric oxide (NO) production decreased, accompanied by a decreased expression of endogenous NO synthase (eNOS). The expression of vascular growth factor (VEGF) and placental growth factor (PLGF) in the maternal blood during the third trimester and umbilical cord of the FGR group was lower than the control group. The PLGF levels in the placentas of the FGR group were also reduced, while the expression of soluble fms-like tyrosine kinase-1 (sFlt-1) increased. In in vitro cell experiments, NO production was obviously lower when the cells were exposed to 100 μM of ADMA, with no difference in eNOS expression. There was a dose-dependent decrease in PLGF expression with increasing doses of ADMA, and the levels of sFlt-1 increased. Moreover, we confirmed that tube formation in HUVECs was lower after ADMA treatment compared with the control group.

Conclusion

The accumulation of ADMA during pregnancy has an adverse effect on fetal development via interference with placental endothelial function and angiogenesis.

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Acknowledgments

We would like to thank all subjects who have agreed to participate in the study, as well as the staff at the Beijing Obstetrics and Gynecology Hospital, Capital Medical University and Beijing Maternal and Child Health Care Hospital who participated in the establishment of the birth cohort.

Funding

This work was supported by Grant No 81571130090 from the China’s National Natural Science Foundation Program.

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Authors and Affiliations

  1. Beijing Obstetrics and Gynecology Hospital, Capital Medical University, 251# Yao Jia Yuan Road, Chao Yang District, Beijing, 100026, China

    Yan Dai, Jun Zhang, Rong Liu, Na Xu, Song-Biao Yan, Yi Chen & Tian-He Li

Authors
  1. Yan Dai
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  2. Jun Zhang
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  3. Rong Liu
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  4. Na Xu
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  5. Song-Biao Yan
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  6. Yi Chen
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  7. Tian-He Li
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Contributions

YD: project development, experimental performation, data collection or management, data analysis, manuscript writing. JZ and RL: data collection or management, data analysis, manuscript writing. NX and SBY: data collection or management, data analysis, manuscript editing. YC and THL: project development, experimental design, data collection or management, data analysis, manuscript writing or editing.

Corresponding authors

Correspondence to Yi Chen or Tian-He Li.

Ethics declarations

The protocol for this study has been approved by the Medical Ethics Committee of the Beijing Obstetrics and Gynecology Hospital, Capital Medical University (ethics number 2016-KY-059-01).

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

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The authors declare that they have no conflict of interest.

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Dai, Y., Zhang, J., Liu, R. et al. The role and mechanism of asymmetric dimethylarginine in fetal growth restriction via interference with endothelial function and angiogenesis. J Assist Reprod Genet 37, 1083–1095 (2020). https://doi.org/10.1007/s10815-020-01750-5

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  • DOI: https://doi.org/10.1007/s10815-020-01750-5

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