Abstract
Stress urinary incontinence (SUI) is a common hygienic problem affecting the quality of women's life worldwide. In this research, we revealed the involvement and regulation of extracellular matrix (ECM) remodeling, oxidative damage, and TGF-β1 signaling in the pathological mechanisms of mechanical trauma-induced SUI. We found that excessive mechanical strain significantly increased apoptosis rate, decreased cell viability and ECM production, and broke the balance of MMPs/TIMPs compared with the nonstrain control (NC) group. The expression levels of TGFβ1, p-Smad3, Nrf2, GPx1, and CAT were downregulated, the production of ROS, 8-OHdG, 4-HNE, and MDA was increased, and the nuclear translocation of Smad2/3 was suppressed after 5333 μstrain's treatment. Both mTGF-β1 pretreatment and Nrf2 overexpression could reverse mechanical injury-induced TGFβ1/Smad3 signaling inhibition and ECM remodeling, whereas mTGF-β1 had no effect on Nrf2 expression. Nrf2 overexpression significantly alleviated mechanical injury-induced ROS accumulation and oxidative damage; in contrast, Nrf2 silencing exhibited opposite effects. Besides, vaginal distention- (VD-) induced in vivo SUI model was used to confirm the in vitro results; Nrf2 knockout aggravates mechanical trauma-induced LPP reduction, ECM remodeling, oxidative damage, and TGF-β1/Smad3 suppression in mice. Therefore, we deduce that mechanical injury-induced ECM remodeling might be associated with Nrf2/ARE signaling suppression mediating TGF-β1/Smad3 signaling inhibition. This might reflect a new molecular target for SUI researches.
Highlights
Stress urinary incontinence (SUI) is a common social and hygienic problem affecting the quality of life of women worldwide and causing serious social economic load [1, 2]
With regard to the metabolism of extracellular matrix (ECM), some studies showed an increase of matrix synthesis in response to suitable mechanical strain [6, 7], while excessive force would reduce the production of ECM [8], which may be one of the main pathological mechanism of childbirth trauma-induced SUI
These results revealed a biphasic effect of cyclic mechanical strain (CMS) on L929 fibroblast
Summary
SUI is a common social and hygienic problem affecting the quality of life of women worldwide and causing serious social economic load [1, 2]. The most recognized theory of the pathogenesis of SUI is the integral theory, which indicated that mechanical trauma-induced ligament and nerve injury, as well as the damage to the vaginal wall and its suspensory structures, resulting from vaginal delivery is one of the widely recognized risk factors of SUI genesis in women [3, 4]. The vesical neck and urethra are attached to the anterior vaginal wall, which has fascial connections to the levator ani muscles through the arcus tendineus fasciae pelvis. Mechanical injury of the pelvic floor (such as childbirth) may disrupt these supportive tissues and connections via the remodeling of ECM. The urethra will lose the hammock-like support and result in SUI. With regard to the metabolism of ECM, some studies showed an increase of matrix synthesis in response to suitable mechanical strain [6, 7], while excessive force would reduce the production of ECM [8], which may be one of the main pathological mechanism of childbirth trauma-induced SUI
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