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

Tze‐Sing Huang,Teh‐Ying Chou,Chih‐Yao Chen,Hsin‐Yi Lan,Peng‐Hui Wang,Hsiao‐Wen Tsai,Chun‐Chung Lee,Ben‐Shian Huang,Hsin‐Yang Li,Ming‐Shyen Yen,Yi‐Jen Chen,Muh‐Hwa Yang,Nae‐Fang Twu,Kuan‐Chong Chao,Cheng‐Hsuan Chang

doi:10.1111/jcmm.12300

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.

Highlights

Adenomyosis is defined as the presence of endometrial glandular tissue in the myometrium and smooth muscle hyperplasia, which remains an important cause of menorrhagia, dysmenorrhoea and preterm labour in women of reproductive age [1, 2]
Because the level of E2 is higher in the secretory phase compared with the early proliferative phase and E2 induces Epithelial–mesenchymal transition (EMT) in endometrial epithelial cells [5], we speculated the VEGF expression profile and Microvascular density (MVD) would be different among different menstrual phases
The result demonstrated that increased vascularization index (VI) and vascularity flow index (VFI) were observed in the secretory phase of the normal control group and adenomyosis patients compared with the proliferative phase (Fig. S1)

Summary

Introduction

Adenomyosis is defined as the presence of endometrial glandular tissue in the myometrium and smooth muscle hyperplasia, which remains an important cause of menorrhagia, dysmenorrhoea and preterm labour in women of reproductive age [1, 2]. Accumulated evidence supports the role of oestrogen in the angiogenesis of normal uterine tissues [9]. A marked reduction in VEGF levels was shown in the endometrial glandular epithelial and stromal cells after oophorectomy of baboons and rhesus monkeys [10, 11], and administration of estradiol (E2) restored VEGF expression and microvascular permeability, which are the early events of angiogenesis [9]. VEGF is inducible by oestrogen in endometrial epithelial cells [12], and can be intensively expressed in the endometrial glandular tissues [13, 14]. The pathogenic role of oestrogenstimulated angiogenesis in the development of adenomyosis remains unclear

Methods

Results

Conclusion