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CXCL1 stimulates decidual angiogenesis via the VEGF-A pathway during the first trimester of pregnancy

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Abstract

Angiogenesis is critical to establishing a successful pregnancy. The chemokine (C-X-C motif) ligand 1 (CXCL1) is a small cytokine belonging to the CXC chemokine family that is an important chemokine involved in the processes of angiogenesis and arteriogenesis; however, little is known about its role in decidual angiogenesis. Effects of CXCL1 on cell proliferation and migration (propidium iodide staining and wound healing assays) of HUVEC cells were determined. The angiogenesis roles of CXCL1 in HUVEC-HTR8/SVneo co-culture system were detected by the tube formation assay. Signal transduction pathways in HUVEC cells in response to CXCL1 were determined by in-cell western analyses. In vivo, mice were injected with (1) PBS (Group A) or (2) CXCL1-neutralizing antibody (Group B) or (3) CXCL1-neutralizing antibody plus recombinant VEGF-A protein (Group C) from E1 to E5 and sacrificed at E6.5 of pregnancy. The decidual angiogenesis in mice was examined by immunohistochemistry of cluster designation 34 (CD34), and the expression levels of vascular endothelial growth factor-A (VEGF-A) in the decidual cells and vascular endothelial growth factor receptor 2 (VEGFR2) in decidual vascular endothelial cells were also tested. Exogenous recombinant human CXCL1 supported endothelial cell proliferation and migration, and this effect was blocked by CXCL1-neutralizing antibody or CXCR2 inhibitor SB265610. The tube formation of HUVEC-HTR8/SVneo co-culture system was significantly stimulated by CXCL1, but this effect was markedly abrogated once they were pretreated with CXCL1-neutralizing antibody or CXCR2 inhibitor SB265610. In addition, the level of vascular endothelial growth factor A (VEGF-A) expression in HUVEC cells was increased by CXCL1, and this level was suppressed by CXCL1-neutralizing antibody or CXCR2 inhibitor SB265610. In vivo, compared with Group A (n = 3), decidual angiogenesis was significantly reduced in Group B by CD34 immunostaining. But compared with Group B, decidual angiogenesis was significantly increased in Group C. In addition, the expression of VEGF-A and VEGFR2 was significantly increased after neutralizing of CXCL1 in Group B. In conclusions, CXCL1 may play essential roles in decidual angiogenesis during the first trimester, and this function may be mediated in part via altering VEGF-A expression.

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Acknowledgements

The authors would like to thank all of the participants who donated decidua and villous tissues for use in this study and the staff in affiliated hospital of Liaoning Province Research Institute of Family Planning who assisted in collecting decidual and villous tissues.

Funding

This work was supported by Natural Science Foundation Program of Liaoning Province (No. 2019-ZD-1093 and No. 2018225087) and Shenyang Young and Middle-aged Science and Technology Innovation Talent Support Project (No. RC180301).

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Authors and Affiliations

  1. Key Laboratory of Reproductive Health and Medical Genetics, National Health and Family Planning Commission, Liaoning Province Research Institute of Family Planning, China Medical University, 10 PuHe Street, Huanggu District, Shenyang, 110031, China

    Chao Ma, Guangxing Liu, Wei Liu, Wei Xu, Hongtu Li, Shuhua Piao, Yang Sui & Wenhua Feng

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  1. Chao Ma
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  2. Guangxing Liu
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  3. Wei Liu
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Correspondence to Wenhua Feng.

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The study was approved by the Ethics Committee of Liaoning Province Research Institute of Family Planning.

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Ma, C., Liu, G., Liu, W. et al. CXCL1 stimulates decidual angiogenesis via the VEGF-A pathway during the first trimester of pregnancy. Mol Cell Biochem 476, 2989–2998 (2021). https://doi.org/10.1007/s11010-021-04137-x

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  • DOI: https://doi.org/10.1007/s11010-021-04137-x

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