Microarray analysis of differentially expressed genes in vaginal tissues from women with stress urinary incontinence compared with asymptomatic women

Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305-5317, USA.
Human Reproduction (Impact Factor: 4.59). 02/2006; 21(1):22-9. DOI: 10.1093/humrep/dei276
Source: PubMed

ABSTRACT The pathophysiology of pelvic floor dysfunction resulting in stress urinary incontinence (SUI) in women is complex. Evidence suggests that there is also a genetic predisposition towards SUI. We sought to identify differentially expressed genes involved in extracellular matrix (ECM) metabolism in vaginal tissues from women with SUI in the secretory phase of menses compared with asymptomatic women.
Tissue samples were taken from the periurethral vaginal wall of five pairs of premenopausal, age-matched SUI and continent women and subjected to microarray analysis using the GeneChip Human Genome U133 oligonucleotide chip set.
Extensive statistical analyses generated a list of 79 differentially expressed genes. Elafin, keratin 16, collagen type XVII and plakophilin 1 were consistently identified as up-regulated ECM genes. Elafin, a serine protease inhibitor involved in the elastin degradation pathway and wound healing, was expressed in pelvic fibroblasts and confirmed by Western blot, quantitative competitive PCR and immunofluorescence cell staining.
Genes involved in elastin metabolism were differentially expressed in vaginal tissue from women with SUI, suggesting that elastin remodelling may be important in the molecular aetiology of SUI.

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Available from: Yan Wen, May 13, 2014
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    • "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] [14] [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. "
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    ABSTRACT: 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. 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. 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. SUI following vaginal trauma involves over-expression of LOX and decreased synthesis of extracellular matrix components or increased proteolysis in the urethra.
    European journal of obstetrics, gynecology, and reproductive biology 05/2012; 163(2):224-9. DOI:10.1016/j.ejogrb.2012.04.012 · 1.63 Impact Factor
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    • "VD in mice could be more useful in future when trangenic models are combined with VD to investigate the genetic dependence of SUI in women after delivery. For example, elastin metabolism can be altered in women with SUI (Chen et al. 2006), and mice with genetically altered elastin metabolism can develop pelvic organ prolapse and decreased LPP after pup delivery (Lee et al. 2008). Combining this genetic model with VD could potentially elucidate the mechanism of elastin recovery after childbirth and identification of women at high risk for SUI. "
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    ABSTRACT: Stress urinary incontinence (SUI) is a common health problem significantly affecting the quality of life of women worldwide. Animal models that simulate SUI enable the assessment of the mechanism of risk factors for SUI in a controlled fashion, including childbirth injuries, and enable preclinical testing of new treatments and therapies for SUI. Animal models that simulate childbirth are presently being utilized to determine the mechanisms of the maternal injuries of childbirth that lead to SUI with the goal of developing prophylactic treatments. Methods of assessing SUI in animals that mimic diagnostic methods used clinically have been developed to evaluate the animal models. Use of these animal models to test innovative treatment strategies has the potential to improve clinical management of SUI. This chapter provides a review of the available animal models of SUI, as well as a review of the methods of assessing SUI in animal models, and potential treatments that have been tested on these models.
    Handbook of experimental pharmacology 01/2011; 202(202):45-67. DOI:10.1007/978-3-642-16499-6_3
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    • "The combined uterine and upper vaginal support is derived from fibers in the paracolpium that are continuations of the cardinal and uterosacral ligaments (USL) (DeLancey, 1992). Although some investigators propose the use of readily available and more distal vaginal biopsies to represent the pelvic connective tissue, rather than the USL (Chen et al., 2006), others have shown the vaginal connective tissue may be more subject to the effects of POP than the proximal USL (Kokcu et al., 2002; Phillips et al., 2006). Likewise, the round ligament (RL), attached high in the pelvis to the fundus of the uterus, is part of the contiguous pelvic fibromuscular connective tissue (Ozdegirmenci et al., 2005), thought to provide orientation of the uterus and is potentially less subject to the traumatic effects of vaginal protrusion in POP than the lower genital tract and vagina. "
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    ABSTRACT: It was hypothesized that the processes contributing to pelvic organ prolapse (POP) may be identified by transcriptional profiling of pelvic connective tissue in conjunction with light microscopy. In order to test this, we performed a frequency-matched case-control study of women undergoing hysterectomy for POP and controls. Total RNA, extracted from uterosacral and round ligament samples used to generate labeled cRNA, was hybridized to microarrays and analyzed for the expression of 32 878 genes. Significance Analysis of Microarrays (Stanford University, CA, USA) identified differentially expressed genes used for ontoanalysis. Quantitative PCR (qPCR) confirmed results. Light microscopy confirmed the tissue type and assessed inflammatory infiltration. The analysis of 34 arrays revealed 249 differentially expressed genes with fold changes (FC) larger than 1.5 and false discovery rates < or =5.2%. Immunity and defense was the most significant biological process differentially expressed in POP. qPCR confirmed the elevated steady-state mRNA levels for four genes: interleukin-6 (FC 9.8), thrombospondin 1 (FC 3.5) and prostaglandin-endoperoxide synthase 2 (FC 2.4) and activating transcription factor 3 (FC 2.6). Light microscopy showed all the samples were composed of fibromuscular connective tissue with no inflammatory infiltrates. In conclusion, genes enriched for 'immunity and defense' contribute to POP independent of inflammatory infiltrates.
    Molecular Human Reproduction 01/2009; 15(1):59-67. DOI:10.1093/molehr/gan074 · 3.48 Impact Factor
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