transforming-growth-factor-beta and Urinary-Incontinence--Stress

We describe current knowledge about collagen/elastin and extracellular matrix metabolism in the genitourinary tract with special emphasis on stress urinary incontinence. We also explored the influence of genetics and reproductive hormones on extracellular matrix metabolism.. We performed a MEDLINE® search from 1995 to February 2011 using the key words stress urinary incontinence, pelvic organ prolapse, extracellular matrix, collagen, elastin, matrix metalloproteinase, collagenase, tissue inhibitors of matrix metalloproteinase, elastin metabolism, elastase, connective tissue, supportive tissue, mechanical stress, biomechanical properties, selective estrogen receptor modulators, transforming growth factor-β and wound healing.. The literature searched produced data on 4 areas of significance for extracellular matrix metabolism in patients with stress urinary incontinence and prolapse, including collagen, elastin and transforming growth factor-β. Data on collagen metabolism continue to support the hypothesis of increased turnover involving matrix metalloproteinases and serine proteases in pelvic tissues of affected individuals. Elastin metabolism studies suggest increased degradation but also abnormal elastin fiber synthesis. Epidemiological data indicate a genetic predisposition to abnormal extracellular matrix in affected individuals while human tissue and animal models reveal differential expression of candidate genes involved in structural proteins. Transforming growth factor-β pathways have been documented to be involved in stress urinary incontinence in human tissues and animal models. Finally, these extracellular matrix metabolisms are modulated by reproductive hormones and selective estrogen receptor modulators.. Pelvic tissue from women with stress urinary incontinence and pelvic organ prolapse show a genetic predisposition to abnormal extracellular matrix remodeling, which is modulated by reproductive hormones, trauma, mechanical stress load and aging. This progressive remodeling contributes to stress urinary incontinence/pelvic organ prolapse by altering normal tissue architecture and mechanical properties.

Topics: Animals; Collagen; Connective Tissue; Cystocele; Elastin; Estrogens; Extracellular Matrix; Humans; Matrix Metalloproteinase 2; Stress, Mechanical; Transforming Growth Factor beta; Urinary Incontinence, Stress

Stress urinary incontinence (SUI) is a common condition in women and associated with extra-cellular matrix (ECM) reconstruction, which is mainly regulated by fibroblasts. However, the underlying mechanism remains obscure. Small extracellular vesicles (sEVs) play fundamental biological roles in various cellular functions. Some studies suggested that the sEVs were involved in the metabolism of ECM and the function of fibroblasts. The purpose of our study was to investigate the effect of sEVs secreted by vaginal fibroblasts on the pathogenesis of SUI. We showed that the fibroblasts of female anterior vaginal wall secreted sEVs. Moreover, fibroblasts of females with SUI had significantly elevated secretion of sEVs. The collagen contents, proliferation and migration capacity of fibroblasts were decreased when fibroblasts were co-cultured with fibroblasts-derived sEVs (fibroblast-sEVs) from SUI patients. Proteomic analysis revealed that fibroblast-sEVs contained various differentially expressed proteins including TIMP2, TGF-β and ABCC4, which were involved in signaling pathways of fibroblasts regulation. Therefore, we suggested that fibroblast-sEVs contributed to the pathogenesis of SUI through various proteins including TIMP2, TGF-β and ABCC4.

Topics: Cell Movement; Cell Proliferation; Cells, Cultured; Collagen; Extracellular Matrix; Extracellular Vesicles; Female; Fibroblasts; Humans; Multidrug Resistance-Associated Proteins; Proteomics; Signal Transduction; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta; Urinary Incontinence, Stress; Vagina

Topics: Animals; Collagen; Connective Tissue; Cystocele; Elastin; Extracellular Matrix; Humans; Transforming Growth Factor beta; Urinary Incontinence, Stress

The molecular mechanisms underlying stress urinary incontinence (SUI) at the tissue level are poorly understood.. To study genetic and molecular alterations in the urethras of animals with experimentally induced SUI.. Cohort analysis of primiparous 2-month-old female Sprague-Dawley rats with experimentally induced SUI versus those who did not develop SUI in a university research laboratory setting.. Rats underwent intravaginal balloon dilation within 24 hours of parturition followed by bilateral ovariectomy one week later. Transvesical cystometry was performed 12 weeks after parturition. Rats were classified as continent (C) or incontinent (I) according to the results of cystometry.. The expression of over 22,000 genes in urethral tissue from the two groups was assessed with the use of an oligo microarray. The expression of relevant genes was confirmed by real-time polymerase chain reaction. Protein expression of small mothers against decapentaplegic 2 (Smad2), one of the differentially expressed genes, was extensively studied by immunohistochemistry and Western blot analysis. Regulation of Smad2 activity by transforming growth factor-beta (TGF-beta) was assessed in cultured urethral smooth muscle cells (USMCs).. After intervention, 14 (58.3%) rats remained continent and 10 (41.7%) became incontinent. There were significant differences in the expression of 42 urethral genes between continent and incontinent rats. The expression of genes involved in the TGF cellular signaling pathway (Smad2), collagen breakdown (matrix metalloproteinase 13 [Mmp13]), and smooth muscle inhibition (regulator of G-protein signaling 2 [Rgs2]) was significantly increased in the incontinent group. SMAD2 protein expression was significantly upregulated in the incontinent rats. In cultured USMCs, SMAD2 phosphorylation and nuclear translocation increased after Tgf-beta treatment.. Genes important in inflammation, collagen breakdown, and smooth muscle inhibition are upregulated in the urethras of female rats with parturition-associated incontinence.

Topics: Animals; Blotting, Western; Disease Models, Animal; Female; Gene Expression Regulation; Immunohistochemistry; Molecular Biology; Myocytes, Smooth Muscle; Parturition; Pregnancy; Pregnancy, Animal; Probability; Protein Array Analysis; Random Allocation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Smad2 Protein; Transforming Growth Factor beta; Urinary Incontinence, Stress

Topics: Animals; Disease Models, Animal; Female; Gene Expression Regulation; Molecular Biology; Parturition; Pregnancy; Pregnancy, Animal; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Smad2 Protein; Transforming Growth Factor beta; Urinary Incontinence, Stress

Topics: Animals; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Molecular Biology; Parturition; Pregnancy; Rats; Rats, Sprague-Dawley; Smad2 Protein; Transforming Growth Factor beta; Urinary Incontinence, Stress

To evaluate differential expression of transforming growth factor (TGF-beta1), latent transforming factor-binding proteins (LTBP-1, LTBP-2) and elastin microfibril components (fibrillin-1 and fibrillin-2) in vaginal tissue from women with stress urinary incontinence (SUI).. In this case-control study, vaginal tissue from women in both phases of the menstrual cycle was obtained. Messenger RNA (mRNA) expressions of LTBP-1, LTBP-2, fibrillin-1, fibrillin-2 and TGF-beta1 were determined by relative real-time quantification PCR. Tissue localization was analysed by immunohistochemistry, and semiquantitative protein expression was evaluated by Western blot analysis.. Vaginal wall fibroblasts synthesized all proteins tested. LTBP-1, LTBP-2 and TGF-beta1 co-localized with elastin microfibrils, fibrillin-1 and fibrillin-2 in the extracellular matrix. LTBP-1 mRNA and protein expressions were higher in control versus women affected with SUI in the proliferative phase (P = 0.04), while in the secretory phase, mRNA expression in cases was higher (P = 0.04). Fibrillin-1 mRNA was higher in women affected by SUI versus controls in both phases, but no statistical differences in fibrillin-1 protein expression were observed between the two groups in either phase. LTBP-2 and TGF-beta1 mRNA expressions showed the same trends as LTBP-1.. LTBP-1, LTBP-2, TGF-beta1, fibrillin-1, and fibrillin-2 expressions are hormonally regulated in vaginal wall fibroblasts and differ in women affected by SUI when compared to controls. These data suggest a mechanism to regulate TGF-beta1 activity in pelvic connective tissue.

Topics: Case-Control Studies; Connective Tissue; Elastin; Extracellular Matrix Proteins; Female; Fibrillin-1; Fibrillin-2; Fibrillins; Fibroblasts; Gonadal Hormones; Humans; Intracellular Signaling Peptides and Proteins; Latent TGF-beta Binding Proteins; Microfibrils; Microfilament Proteins; Pelvis; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Urinary Incontinence, Stress; Vagina