The integrity of the structure and function of the endometrium is essential for the maintenance of fertility. However, the repair mechanisms of uterine injury remain largely unknown. Here, we showed that the disturbance of mechanical cue homeostasis occurs after uterine injury. Applying a multimodal approach, we identified YAP as a sensor of biophysical forces that drives endometrial regeneration. Through protein activation level analysis of the combinatorial space of mechanical force strength and of the presence of particular kinase inhibitors and gene silencing reagents, we demonstrated that mechanical cues related to extracellular matrix rigidity can turn off the Rap1a switch, leading to the inactivation of ARHGAP35and then induced activation of RhoA, which in turn depends on the polymerization of the agonist protein F-actin to activate YAP. Further study confirmed that mechanotransduction significantly accelerates remodeling of the uterus by promoting the proliferation of endometrial stromal cells in vitro and in vivo. These studies provide new insights into the dynamic regulatory mechanisms behind uterine remodeling and the function of mechanotransduction.

中文翻译：

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细胞外基质硬度通过 Rap1a/ARHGAP35/RhoA/F-actin/YAP 轴介导子宫修复

子宫内膜结构和功能的完整性对于维持生育能力至关重要。然而，子宫损伤的修复机制仍然很大程度上未知。在这里，我们发现子宫损伤后会发生机械提示稳态的紊乱。应用多模式方法，我们将 YAP 确定为驱动子宫内膜再生的生物物理力传感器。通过对机械力强度的组合空间以及特定激酶抑制剂和基因沉默试剂的存在进行蛋白质激活水平分析，我们证明与细胞外基质刚性相关的机械信号可以关闭 Rap1a 开关，导致 ARHGAP35 失活，然后诱导 RhoA 激活，而 RhoA 又依赖于激动剂蛋白 F-肌动蛋白的聚合来激活 YAP。进一步的研究证实，机械转导通过促进体内外子宫内膜基质细胞的增殖，显着加速子宫重塑。这些研究为子宫重塑背后的动态调节机制和力转导功能提供了新的见解。