Oestrogen-induced angiogenesis promotes adenomyosis by activating the Slug-VEGF axis in endometrial epithelial cells.
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.
National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
Tze-Sing
TS
Huang
Yi-Jen
YJ
Chen
Teh-Ying
TY
Chou
Chih-Yao
CY
Chen
Hsin-Yang
HY
Li
Ben-Shian
BS
Huang
Hsiao-Wen
HW
Tsai
Hsin-Yi
HY
Lan
Cheng-Hsuan
CH
Chang
Nae-Fang
NF
Twu
Ming-Shyen
MS
Yen
Peng-Hui
PH
Wang
Kuan-Chong
KC
Chao
Chun-Chung
CC
Lee
Muh-Hwa
MH
Yang
D062788:Adenomyosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004715:Endometriosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004967:Estrogens / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D004967:Estrogens; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
Slug; adenomyosis; angiogenesis; epithelial-mesenchymal transition; oestrogen