Huang Tze-Sing, Chen Yi-Jen, Chou Teh-Ying, Chen Chih-Yao, Li Hsin-Yang, Huang Ben-Shian, Tsai Hsiao-Wen, Lan Hsin-Yi, Chang Cheng-Hsuan, Twu Nae-Fang, Yen Ming-Shyen, Wang Peng-Hui, Chao Kuan-Chong, Lee Chun-Chung, Yang Muh-Hwa
National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
J Cell Mol Med. 2014 Jul;18(7):1358-71. doi: 10.1111/jcmm.12300. Epub 2014 Apr 24.
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.
子宫腺肌病是一种雌激素依赖性疾病，其特征在于子宫内膜上皮细胞侵入子宫肌层，并且血管生成被认为是子宫腺肌病发病机制中子宫内膜腺组织植入所必需的。在本研究中，我们证明，与在位内膜相比，通过超声检查发现子宫腺肌病病灶的血管增多。在显微镜下，病灶还表现出与雌激素相关的微血管密度升高以及子宫内膜上皮细胞中VEGF表达增加。我们之前报道过，雌激素诱导的Slug表达对于子宫内膜上皮-间质转化和子宫腺肌病的发展至关重要。我们目前的研究表明，雌二醇（E2）在内膜上皮细胞中引发了Slug-VEGF轴，并且还诱导了血管内皮细胞中的促血管生成活性。针对E2或VEGF的拮抗剂抑制了内皮细胞迁移和管腔形成。动物实验进一步证实，阻断E2或VEGF可有效减弱子宫腺肌病病灶的植入。这些结果突出了雌激素诱导的血管生成在子宫腺肌病发展中的重要性，并提供了一种通过阻断E2-Slug-VEGF途径治疗子宫腺肌病的潜在策略。
