Synergistic Effect of Vaginal Trauma and Ovariectomy in a Murine Model of Stress Urinary Incontinence: Upregulation of Urethral Nitric Oxide Synthases and Estrogen Receptors

Abstract

The molecular mechanisms underlying stress urinary incontinence (SUI) are unclear. We aimed to evaluate the molecular alterations in mice urethras following vaginal trauma and ovariectomy (OVX). Twenty-four virgin female mice were equally distributed into four groups: noninstrumented control; vaginal distension (VD) group; OVX group; and VD + OVX group. Changes in leak point pressures (LPPs), genital tract morphology, body weight gain, plasma 17β-estradiol level and expressions of neuronal nitric oxide synthase (nNOS), induced nitric oxide synthase (iNOS), and estrogen receptors (ERs—ERα and ERβ) were analyzed. Three weeks after VD, the four groups differed significantly in genital size and body weight gain. Compared with the control group, the plasma estradiol levels were significantly decreased in the OVX and VD + OVX groups, and LPPs were significantly decreased in all three groups. nNOS, iNOS, and ERα expressions in the urethra were significantly increased in the VD and VD + OVX groups, whereas ERβ expression was significantly increased only in the VD + OVX group. These results show that SUI following vaginal trauma and OVX involves urethral upregulations of nNOS, iNOS, and ERs, suggesting that NO- and ER-mediated signaling might play a role in the synergistic effect of birth trauma and OVX-related SUI pathogenesis.

Potential therapeutic role of punicalagin against mechanical-trauma-induced stress urinary incontinence via upregulation of Nrf2 and TGF-β1 signaling

“…Oxidative damage to vaginal wall and urethral sphincter was confirmed as a result of mechanical trauma and was prominent in the pathological process of pelvic floor dysfunction (PFD) [ 7 – 11 ]. Previous study indicated that cyclic mechanical strain increased oxidative damage to human parametrial ligament fibroblasts and may be a pathogenesis of PFD [ 30 ].…”

“…Aging, vaginal childbirth, declined hormonal status (menopause), and obesity were the main risk factors of SUI [ 4 – 6 ]. Increasing research confirmed that mechanical-trauma-induced oxidative damage and extracellular matrix (ECM) remodeling are probably involved in the pathogenesis of SUI, especially birth trauma and increased abdominal-pressure-induced SUI or pelvic organ prolapase (POP) with SUI [ 7 – 11 ]. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is an upstream transcription factor modulating antioxidant ability [ 12 ].…”

Sulforaphane Treatment of Stress Urinary Incontinence Via the Nrf2-ARE Pathway in a Rat Model

“…Prolonged elevated pressure and intravaginal distention may cause ischemia damage to the urethra sphincter. Ischemia in turn induces oxidative stress reactions, resulting in urethral relaxation and an estrogen deficiency that increases oxidative expression and decreases urethral trophicity [11]. The use of antioxidants, such as SFN, may ameliorate oxidative stress reaction-induced SUI.…”

“…Vaginal delivery-caused birth trauma and menopause are widely recognized risk factors for SUI genesis in women [10]. A recent study implicated oxidative stress in the synergistic effect of birth trauma and menopause-related SUI pathogenesis [11]. However, there are no reports of the treatment of SUI with sulforaphane (SFN), let alone studies explaining the exact mechanism.…”

Review of Animal Models to Study Urinary Bladder Function

“…This information provided molecular mechanism of urethra responded to SUI. Synergistic VD and ovariectomy to study SUI in mice model was performed by Chen et al [ 81 ]. Estrogen receptor and nitric oxide mediated signal pathways were found to be involved in the pathogenesis of SUI.…”