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

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.

Proangiogenic features in chronic pelvic pain caused by adenomyosis

“…It is a common cause of pelvic pain, abnormal uterine bleeding and abortion in women of reproductive age [1][2][3]. Some researchers proved the presence of paracrine changes of angiogenesis in adenomyosis, namely, a shift toward angiogenesis the pro-angiogenic components.…”

Hormone Use is Associated with Lymphovascular Invasion in Breast Cancer

“…Tamoxifen, which is a selective estrogen receptor modulator, for the treatment of breast cancer has the opposite effect compared with estrogen. In other words -HRT and OC seem to provide an angiogenesis in the tumor while tamoxifen causes the (Garvin et al, 2005;Huang et al, 2014). LVI is a predictor of recurrence and survival in the disease (Sanchez et al, 2010;Zhao et al, 2012;Scoppmann et al, 2013) and thus an important prognostic marker.…”

“…Endothelial growth factor (VEGF) can be a key mediator in tumour angiogenesis according Stoner et al, 2004;Garvin et al, 2005;Widodo et al, 2013;Huang et al, 2014. Tamoxifen, which is a selective estrogen receptor modulator, for the treatment of breast cancer has the opposite effect compared with estrogen.…”

Oestrogen-Induced Angiogenesis and Implantation Contribute to the Development of Parasitic Myomas after Laparoscopic Morcellation

“…Because uterine myoma is also known as an oestrogen-dependent disorder, fresh UM samples were fragmented into 1-2 mm diameter sections under sterile conditions. The fragments were cultured in Dulbecco's Modified Eagle's Medium (DMEM) + Ham's F12 (1 : 1) +10 % fetal bovine serum (FBS) supplemented with E2 (10 −9 M) (Sigma-Aldrich, St. Louis, MO) for 4 h prior to xenograft into 8-week-old NOD-SCID female mice [32,33]. One 1-cm longitudinal incision at the lower abdomen of SCID mice was made and ten UM fragments were implanted in the four quadrants of the peritoneal cavity.…”