Hypoxia Promotes Ectopic Adhesion Ability of Endometrial Stromal Cells via TGF-β1/Smad Signaling in Endometriosis
Hypoxia Promotes Ectopic Adhesion Ability of Endometrial Stromal Cells via TGF-β1/Smad Signaling in Endometriosis
复制标题
子宫内膜异位症中缺氧通过 TGF-β1/Smad 信号传导促进子宫内膜基质细胞的异位粘附能力。
DOI：
10.1210/en.2017-03227
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发表时间：
2018-04-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Songying
中科院分区：
文献类型：
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作者：
Lin, Xiang;Dai, Yongdong;Zhang, Songying
缺氧在子宫内膜异位症的进展中起着至关重要的作用。此外，整合素介导的异常粘连对于子宫内膜异位症病变的建立也是必不可少的。在这项研究中，我们试图确定缺氧在子宫内膜异位症中整合素介导的子宫内膜基质细胞（ESCs）粘附中的作用。应用免疫组化方法检测15例正常子宫内膜和15例配对异位和异位子宫内膜中粘附分子整合素(integrin α(5)、integrin α (V)、integrin β（3)、integrin β(5)）的表达。本实验采用低氧（1% O-2）或常氧（21% O-2）环境培养13例腹膜子宫内膜异位症患者增殖期原代ESCs，采用定量逆转录聚合酶链反应和western blot检测缺氧诱导因子(HIF)-1 α、转化生长因子(TGF)- β 1和整合素的表达水平。我们还探讨了子宫内膜异位症小鼠模型中整合素的变化。我们的研究结果表明，与异位和正常子宫内膜的ESCs相比，HIF-1 α和整合素在子宫内膜异位症病变的ESCs中高表达。缺氧处理可显著提高ESC粘附能力和整合素表达，并与tgf - β 1表达呈正相关。tgf - β 1和缺氧均可增强ESC的粘附性能，而缺氧联合tgf - β 1受体抑制剂可抑制ESC的粘附。抑制HIF-1 α可减弱tgf - β 1/Smad信号激活和整合素表达，并降低ESC粘附。HIF-1 α、tgf - β 1和整合素在小鼠子宫内膜异位症囊肿中表达水平较高。我们的研究结果为子宫内膜异位症提供了一个新的视角，即缺氧微环境刺激ESCs产生过多的tgf - β 1，激活tgf - β 1/Smad信号通路，从而增强ESCs的整合素表达和粘附能力。
Hypoxia plays a vital role in the progression of endometriosis. Additionally, integrin-mediated aberrant adhesion is also essential for establishment of endometriotic lesions. In this study, we sought to determine the function of hypoxia in integrin-mediated adhesion of endometrial stromal cells (ESCs) in endometriosis. The expressions of adhesion molecule integrins (integrin alpha(5), integrin alpha(V), integrin beta(3), and integrin beta(5)) were determined in 15 normal endometria and 15 paired eutopic and ectopic endometria by immunohistochemistry. Thirteen primary ESCs from patients with peritoneal endometriosis in the proliferative phase were cultured under a hypoxic (1% O-2) or normoxic (21% O-2) environment, and the expression levels of hypoxia-inducible factor (HIF)-1 alpha, transforming growth factor (TGF)-beta 1, and integrins were detected by quantitative reverse transcription polymerase chain reaction and western blot. The alteration of integrins in endometriotic mouse models were also explored. Our results demonstrated that HIF-1 alpha and integrins were highly expressed in ESCs of endometriotic lesions compared with ESCs of eutopic and normal endometrium. Hypoxia treatment significantly increased ESC adhesion abilities and integrin expression, which were positively correlated with TGF-beta 1 expression. Both TGF-beta 1 and hypoxia enhanced ESC adhesion properties, whereas hypoxia combined with TGF-beta 1 receptor inhibitor inhibited ESC adhesion. Knockdown of HIF-1 alpha attenuated TGF-beta 1/Smad signaling activation and integrin expression and reduced ESC adhesion. Higher expression levels of HIF-1 alpha, TGF-beta 1, and integrins were detected in endometriotic cysts from mice models. Our findings provide a novel insight of endometriosis that the hypoxic microenvironment stimulates ESCs to produce excessive TGF-beta 1 and activates the TGF-beta 1/Smad signaling pathway, thus enhancing integrin expression and the adhesion ability of ESCs.