Stress urinary incontinence following vaginal trauma involves remodeling of urethral connective tissue in female mice Huey-Yi Chen a, *, Yu-Ning Lin b , Yung-Hsiang Chen c , Wen-Chi Chen d a Department of Obstetrics and Gynecology, Sex Hormone Research Center, China Medical University Hospital, Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan b College of Life Science, National Chung Hsing University, Taichung, Taiwan c Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan d Department of Urology, China Medical University Hospital, Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan 1. Introduction Stress urinary incontinence (SUI) is a common disease that is defined as the involuntary leakage of urine under vesical stress conditions such as coughing and sneezing [1]. The primary etiological factor of SUI is vaginal delivery [2], usually due to a combined muscular, nerve and connective tissue injury [3]. Although progress has been made in the treatment of SUI [4], our understanding of the molecular mechanisms underlying the condition is poor. Because of the limited availability of human tissue for study, animal models are an important adjunct in improving our understanding of SUI [5]. Over the last decade, animal models of SUI have increasingly been used to understand the pathogenesis of the condition [6]. Vaginal distension (VD) [7] and pudendal nerve transection [8] have been used for inducing SUI in rats, as evidenced by lowered leak point pressures (LPP) on urodynamic testing. Birth trauma from vaginal delivery may include denervation damage, ischemia and mechanical injuries to the muscular, nervous and connective components of the lower urinary tract tissues [3,9–12]. Recent studies have indicated that in SUI-affected periurethral connective tissues, the metabolism of collagen and elastin is altered [13–15]. Lysyl oxidase (LOX), an extracellular matrix (ECM) remodeling enzyme, is required for the oxidative deamination of lysine residues in collagen and elastin molecules required for fiber cross-linking. Thus, LOX controls both the structure and the tensile strength of the ECM, and is subsequently involved in the preservation of tissue integrity [16]. Mutant mice lacking lysyl oxidase-like-1 (LOXL1) have been demonstrated to develop complex and severe pelvic floor disorders [17–19]. The use of mice in various lines of translational research has made available transgenic and knockout technologies for con- ducting mechanistic studies of various target diseases. The C57BL/ 6 mouse, for example, has been widely used for genetic manipulation in previous studies concerning urinary and pelvic disorders [17–19]. Based on the relevant literature described above, we hypothesized that in a mouse model of SUI: (1) vaginal trauma might induce LOX expression and (2) the metabolism of urethral connective tissue might be altered by vaginal trauma. In order to test these hypotheses, we designed the present study with the following aims: (1) examining LPP in C57BL/6 mice after VD European Journal of Obstetrics & Gynecology and Reproductive Biology xxx (2012) xxx–xxx * Corresponding author at: Department of Obstetrics and Gynecology, China Medical University Hospital, No. 2 Yu-Der Road, Taichung 404, Taiwan. Tel.: +886 4 22052121x2063; fax: +886 4 22033295. E-mail address: d888208@ms45.hinet.net (H.-Y. Chen). A R T I C L E I N F O Article history: Received 9 November 2011 Received in revised form 25 March 2012 Accepted 17 April 2012 Keywords: Stress urinary incontinence Vaginal distension Leak point pressure Collagen Elastin Lysyl oxidase A B S T R A C T Objective: The molecular mechanisms underlying stress urinary incontinence (SUI) are not clear. This study was conducted to evaluate molecular alterations in the urethras of mice with experimentally induced SUI. Study design: Eighteen virgin female mice were equally distributed into three groups as follows: two groups undergoing vaginal distension (VD) for 1 h with 3 mm and 8 mm dilators each, and a non- instrumented control group. Changes in leak point pressure (LPP), morphology, lysyl oxidase (LOX) expression and the metabolism of urethral connective tissue were assessed. Results: The LPP was significantly decreased in the 3 mm and 8 mm VD groups compared with that in the control group. Collagen and elastin expression in the urethra was significantly decreased in the 8 mm VD group compared with that in the control group, while LOX expression was significantly enhanced. Conclusions: SUI following vaginal trauma involves over-expression of LOX and decreased synthesis of extracellular matrix components or increased proteolysis in the urethra. ß 2012 Elsevier Ireland Ltd. All rights reserved. G Model EURO-7694; No. of Pages 6 Please cite this article in press as: Chen H-Y, et al. Stress urinary incontinence following vaginal trauma involves remodeling of urethral connective tissue in female mice. Eur J Obstet Gynecol (2012), http://dx.doi.org/10.1016/j.ejogrb.2012.04.012 Contents lists available at SciVerse ScienceDirect European Journal of Obstetrics & Gynecology and Reproductive Biology jou r nal h o mep ag e: w ww .elsevier .co m /loc ate/ejo g rb 0301-2115/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejogrb.2012.04.012