Oestrogen-induced angiogenesis promotes adenomyosis by activating the Slug-VEGF axis in endometrial epithelial cells

Authors

  • Tze-Sing Huang,

    1. National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
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    • These authors contributed equally to this work.
  • Yi-Jen Chen,

    Corresponding author
    1. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
    2. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
    • Correspondence to: Dr. Muh-Hwa YANG, and Yi-Jen CHEN,

      Institute of Clinical Medicine, National Yang-Ming University,

      No. 155, Li-Nong Street Sec. 2, Taipei 112, Taiwan.

      Tel.: 886-2-28267000 ext. 7911

      Fax: 886-2-28235870

      E-mails: mhyang2@vghtpe.gov.tw; chenyj@vghtpe.gov.tw

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    • These authors contributed equally to this work.
  • Teh-Ying Chou,

    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
    2. Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Chih-Yao Chen,

    1. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Hsin-Yang Li,

    1. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
    2. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
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  • Ben-Shian Huang,

    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
    2. Department of Obstetrics and Gynecology, National Yang-Ming University Hospital, Ilan, Taiwan
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  • Hsiao-Wen Tsai,

    1. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
    2. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
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  • Hsin-Yi Lan,

    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
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  • Cheng-Hsuan Chang,

    1. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Nae-Fang Twu,

    1. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Ming-Shyen Yen,

    1. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Peng-Hui Wang,

    1. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
    2. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
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  • Kuan-Chong Chao,

    1. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Chun-Chung Lee,

    1. National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
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  • Muh-Hwa Yang

    Corresponding author
    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
    2. Division of Hematology-Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
    3. Immunology Research Center, National Yang-Ming University, Taipei, Taiwan
    • Correspondence to: Dr. Muh-Hwa YANG, and Yi-Jen CHEN,

      Institute of Clinical Medicine, National Yang-Ming University,

      No. 155, Li-Nong Street Sec. 2, Taipei 112, Taiwan.

      Tel.: 886-2-28267000 ext. 7911

      Fax: 886-2-28235870

      E-mails: mhyang2@vghtpe.gov.tw; chenyj@vghtpe.gov.tw

    Search for more papers by this author

Abstract

Adenomyosis is an oestrogen-dependent disease characterized by the invasion of endometrial epithelial cells into the myometrium of uterus, and angiogenesis is thought to be required for the implantation of endometrial glandular tissues during the adenomyotic pathogenesis. In this study, we demonstrate that compared with eutopic endometria, adenomyotic lesions exhibited increased vascularity as detected by sonography. Microscopically, the lesions also exhibited an oestrogen-associated elevation of microvascular density and VEGF expression in endometrial epithelial cells. We previously reported that oestrogen-induced Slug expression was critical for endometrial epithelial–mesenchymal transition and development of adenomyosis. Our present studies demonstrated that estradiol (E2) elicited a Slug-VEGF axis in endometrial epithelial cells, and also induced pro-angiogenic activity in vascular endothelial cells. The antagonizing agents against E2 or VEGF suppressed endothelial cells migration and tubal formation. Animal experiments furthermore confirmed that blockage of E2 or VEGF was efficient to attenuate the implantation of adenomyotic lesions. These results highlight the importance of oestrogen-induced angiogenesis in adenomyosis development and provide a potential strategy for treating adenomyosis through intercepting the E2-Slug-VEGF pathway.

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