雌激素-RhoA-ROCK通路激活对子宫腺肌病平滑肌结构与功能的影响及其机制研究

Adenomyosis (ADS) is an estrogen-dependent disease with unclear aetiology that has a tremendous impact on women's well-being and health. There has no effective treatment of adenomyosis, its incidence is rising and the incident age gets younger that makes adenomyosis a formidable clinical problem. At present, in the understanding of the pathophysiology of adenomyosis, structure and function of the junctional zone(JZ) turns out to be of utmost importance. RhoA and its dowmstream effector Rho kinase(ROCK) which controls multiple cellular processes, is involved in the control of smooth muscle cell contractin , proliferation and cytoskeleton function.Our previous study discoverd that the expression of ERα in cultured JZ smooth muscle cells of adenomyosis showed no cyclic change between proliferative phase and secretory, and the expression of ERα was much higher than that of the control. We also demonstrated that estrogen enhanced the expression of RhoA n cultured JZ smooth muscle cells of adenomyosis. Therefore,we propose that estrogen may induce dysfuctional contraction and abnormal structure of JZ smooth muscle by enhancing RhoA/ROCK signaling, that plays a fundamental role in the clinical features of adenomyosis. Our research using flow cytmetry, molecular biotechnology and transmission electron microscope, will focus on estrogen-RhoA-ROCK pathway in the regulation of contraction, proliferation and ultrastructural features of JZ smooth muscle. Our research aiming to explore the pathogenesis of adenomyosis may offer a new target for the prevention and treatment of uterine adenomyosis.

子宫腺肌病（ADS）是严重危害妇女健康的雌激素依赖性疾病，病因机制不清，无有效治疗方法，发病率上升和年轻化趋势已使其成为临床亟待解决难题。目前认为子宫内膜肌层连接带（JZ）平滑肌的收缩与结构异常与腺肌病发病密切相关。RhoA及其下游效应物Rho激酶（ROCK）对调节平滑肌的收缩、增殖和维持正常细胞形态有重要作用。我们前期研究已证实：腺肌病子宫JZ 平滑肌细胞雌激素受体α（ERα）的表达无周期性改变，且呈持续高水平表达；而雌激素又能够使JZ平滑肌细胞RhoA的表达持续增加。由此推测，雌激素通过激活RhoA-ROCK通路，诱导子宫JZ平滑肌细胞收缩与增殖紊乱进而导致其结构异常，是腺肌病发病与临床表现的关键。本研究借助分子生物学、流式细胞分析及透射电镜等技术，聚焦雌激素-RhoA-ROCK通路对子宫JZ平滑肌细胞收缩、增殖及超微结构的作用及其影响，为探讨子宫腺肌病发病机制并为临床治疗提供新靶点。

子宫腺肌病（ADS）是严重危害妇女健康的雌激素依赖性疾病，病因机制不清，无有效治疗方法，发病率上升和年轻化趋势已使其成为临床亟待解决难题。目前认为子宫内膜-肌层交界区，也称子宫结合带（JZ）平滑肌的收缩与结构异常与腺肌病发病密切相关。RhoA及其下游效应物Rho激酶（ROCK）对调节平滑肌的收缩、增殖和维持正常细胞形态有重要作用。本研究借助分子生物学、流式细胞分析和透射电镜等技术观察：(1) 雌激素刺激对RhoA、ROCK1和ROCK2的表达及活性的影响；(2) 在不同水平雌激素-RhoA/ROCK信号条件下，雌激素对平滑肌细胞收缩和增殖功能的影响；(3) RhoA/ROCK信号通路激活引起平滑肌细胞收缩增殖的具体机制; (4)雌激素-RhoA-ROCK激活对JZ平滑肌细胞超微结构的影响.结果发现：(1)雌激素对JZ平滑肌的收缩作用是通过激活RhoA/ROCK通路实现。随着雌激素作用浓度的升高，JZ平滑肌细胞的收缩功能逐渐增强。(2)在腺肌病子宫中，局部聚集的高浓度雌激素通过上调RhoA/ROCK通路使JZ平滑肌收缩效应增强，证明了子宫JZ平滑肌的异常收缩参与了ADS的发生发展。(3)RhoA/ROCK信号通路在JZ平滑肌细胞的增殖功能中也发挥重要的调节作用,雌激素激活RhoA/ROCK信号通路，促进细胞周期G1/S期转化，引起子宫腺肌病JZ平滑肌细胞的异常增殖可能是导致该区域结构和功能异常的重要机制；(4)透射电镜观察显示:腺肌病组JZ肌层细胞增生明显，胞浆丰富，线粒体数量增加、体积增大、空泡化明显。以上研究结果探讨了雌激素-RhoA-ROCK通路的激活在子宫腺肌病JZ平滑肌功能紊乱与结构异常中作用及其机制，并且为进一步明确子宫腺肌病的病因与病理机制提供重要依据，为临床预防腺肌病的发生发展、探求行之有效的治疗方案具有重要的理论意义和应用前景。