Mechanical stress influences the morphology and function of human uterosacral ligament fibroblasts and activates the p38 MAPK pathway

Abstract

Introduction and hypothesis Pelvic organ prolapse (POP) is a common condition in older women that affects quality of life. Mechanical injury of the pelvic floor support system contributes to POP development. In our study, we aimed to examine the mechanical damage to human uterosacral ligament fibroblasts (hUSLFs) to preliminarily explore the mechanism of mechanical transduction in POP. Methods hUSLFs were derived from POP and non-POP patients. Mechanical stress was induced by the FX-5000 T-cell stress loading system. Student’s t-test was used for comparisons between different groups. Results We found that hUSLFs from POP patients were larger and longer than those from non-POP patients and exhibited cytoskeleton F-actin rearrangement. Collagen I and III expression levels were lower and matrix metalloproteinase 1 (MMP1) levels were higher in POP patients than in non-POP patients. Additionally, the apoptosis rate was significantly increased in POP patients compared to non-POP patients. After mechanical stretching, hUSLFs underwent a POP-like transformation. Cells became longer, and the cytoskeleton became thicker and rearranged. The extracellular matrix (ECM) was remodelled because of the upregulation of collagen I and III expression and downregulation of MMP1 expression. Mechanical stress also induced hUSLF apoptosis. Notably, we found that the p38 MAPK pathway was activated by mechanical stretching. Conclusions Mechanical stress induced morphological changes in ligament fibroblasts, leading to cytoskeleton and ECM remodelling and cell apoptosis. p38 MAPK might be involved in this process, providing novel insights into the mechanical biology of and possible therapies for this disease.

The protective effect of 17 β-estradiol on human uterosacral ligament fibroblasts from postmenopausal women with pelvic organ prolapse

“…Alteration in Frontiers in Physiology frontiersin.org cell growth may affect the production of collagen, elastic fibres and ECMs and the associated synthesis or turnover, assembly, cross-linking and remodeling. Actually, in our previous study, decrease of collagens (COLI and COLIII) and increase of Bax in mRNA levels was found in POP hUSLFs (Zhu et al, 2021). Pelvic floor relies on the pelvic floor fascia and ligaments for its support, and the main component of the ligaments is collagen.…”

Advanced glycation end products (AGEs) downregulate the miR-4429/PTEN axis to promote apoptosis of fibroblasts in pelvic organ prolapse

“…Fibroblasts are responsible for the secretion and remodeling of ECM in ECM-rich pelvic connective tissues that primarily support the pelvic organs. The disfunction of fibroblasts resulted in a disordered metabolism of collagen and other ECM proteins (40)(41)(42). Therefore, the increased fibroblast apoptosis could result in reduced collagen expression in POP and contribute to the weakness of supportive tissues in POP (40,43).…”

“…The disfunction of fibroblasts resulted in a disordered metabolism of collagen and other ECM proteins ( 40 - 42 ). Therefore, the increased fibroblast apoptosis could result in reduced collagen expression in POP and contribute to the weakness of supportive tissues in POP ( 40 , 43 ). In the present study, AGEs promoted the apoptosis of fibroblasts from the non-POP group and aggregated the apoptosis of fibroblasts from the POP group, suggesting that AGEs might be a pathogenesis factor that induced the fibroblast apoptosis in POP.…”

SB203580—A Potent p38 MAPK Inhibitor Reduces the Profibrotic Bronchial Fibroblasts Transition Associated with Asthma

“…In this study, we show that the inhibition of p38 MAPK by SB203580 affects the maturation of super mature vinculin-enriched FAs but significantly attenuates the integrin α5 and αV expression levels. Previously, it was shown that the inhibition of p38 MAPK signaling resulted in the abrogation of stretch-induced cytoskeletal reorganization in mouse wild type-derived and human uterosacral ligament fibroblasts [ 63 , 64 ]. On the other hand, other studies report that the status of FA maturation is associated with the ECM composition as well as with the actin cytoskeleton architecture [ 65 , 66 , 67 ].…”