Crosstalk between Extracellular Matrix Stiffness and ROS Drives Endometrial Repair via the HIF-1α/YAP Axis during Menstruation

Abstract

Although the menstrual cycle driven by sex steroid hormones is an uncomplicated physiological process, it is important for female health, fertility and regenerative biology. However, our understanding of this unique type of tissue homeostasis remains unclear. Here, we examined the biological effects of mechanical force by evaluating the changing trend of extracellular matrix (ECM) stiffness, and the results suggested that ECM stiffness was reduced and that breaking of mechanotransduction delayed endometrium repair in a mouse model of simulated menses. We constructed an ECM stiffness interference model in vitro to explain the mechanical force conduction mechanism during endometrial regeneration. We discovered that ECM stiffness increased the expression and nuclear transfer of YAP, which improved the creation of a microenvironment, in a manner that induced proliferation and angiogenesis for endometrial repair by activating YAP. In addition, we observed that physiological endometrial hypoxia occurs during the menstrual cycle and that the expression of HIF-1α was increased. Mechanistically, in addition to the classical F-actin/YAP pathway, we also found that the ROS/HIF-1α/YAP axis was involved in the transmission of mechanical signals. This study provides novel insights into the essential menstrual cycle and presents an effective, nonhormonal treatment for menstrual disorders.