College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230031, People's Republic of China.
Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China.
Cell Commun Signal. 2023 Jan 23;21(1):22. doi: 10.1186/s12964-022-01018-8.
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. Video Abstract.
子宫内膜的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在很大程度上尚不清楚。在这里，我们表明，子宫损伤后会发生机械线索稳态的破坏。通过应用多模态方法，我们确定 YAP 是一种感知生物物理力的传感器，可驱动子宫内膜再生。通过对机械力强度和特定激酶抑制剂及基因沉默试剂存在的组合空间的蛋白质激活水平分析，我们证明了与细胞外基质刚性相关的机械线索可以关闭 Rap1a 开关，导致 ARHGAP35 的失活，然后诱导 RhoA 的激活，而 RhoA 的激活又依赖于激动蛋白 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外和体内子宫内膜基质细胞的增殖，显著加速了子宫的重塑。这些研究为子宫重塑背后的动态调节机制和机械转导的功能提供了新的见解。视频摘要。
