盆腔器官脱垂的比较蛋白质组学研究
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摘要
●研究目的
1.应用双向荧光差异凝胶电泳和质谱技术,建立绝经后POP患者与正常女性主骶韧带的蛋白质表达谱,筛选并鉴定POP患者与正常对照之间的差异表达蛋白。
2.分析差异表达蛋白,探讨POP发生的分子机制。
●材料和方法
1.在绝经状态、年龄、体重指数、产次等影响POP发生的重要因素匹配的前提下,选取5例POP与5例无POP患者的子宫主骶韧带复合体标本。
2.提取组织总蛋白,普通双向电泳分离,银染显色鉴定蛋白质抽提质量以及在胶图上的分布情况,并优化实验方法。
3.荧光染料分别标记POP组、对照组以及内标,进行双向电泳得到双向荧光差异凝胶图谱。同时制作制备胶。对胶图进行匹配和差异分析,筛选出两组之间|AV.Ratio|≥1.5,P<0.05的差异表达蛋白质点。
4.将差异蛋白质点胶内酶解后进行MALDI-TOF质谱分析和数据库搜索,鉴定差异表达的蛋白质点。
●实验结果
1.提取的组织蛋白经定量和普通双向电泳检测,蛋白质浓度符合实验要求,在胶图上分离情况满意,平均可获得1224±22个蛋白质点。
2.获得5张双向荧光差异凝胶电泳胶图,每张胶图上共约1111±54个蛋白质点,经过比较分析筛选出33个差异表达蛋白质点,均在POP组下调,最大下调比例为8.5倍。
3.质谱成功鉴定出12种蛋白,分别是白蛋白、纤维蛋白原、未知蛋白、电子传递黄素蛋白、血红蛋白、载脂蛋白A-I、肌动蛋白、转胶蛋白、丝切蛋白、亲环素A、肌球蛋白、半凝乳素-1。
●结论
1.经过机械研磨、匀浆以及超声破碎即可使韧带组织的提取蛋白质浓度和纯度基本满足实验要求,使用24cm PH3-10非线性胶条可以达到较为理想的蛋白质分离效果。双向电泳可作为筛选POP差异表达蛋白的研究方法。
2.半凝乳素-1和亲环素A在神经损伤修复中发挥重要作用。这两种蛋白在POP组的下调说明盆底神经损伤可能是POP发生的病因之一。
3.电子传递黄素蛋白的减少与线粒体异常相关,线粒体的异常可加重患者盆底组织的衰老程度,增加POP发生的风险。
4.肌动蛋白、转胶蛋白、肌球蛋白和丝切蛋白的下调可导致细胞骨架异常以及收缩功能异常,使POP患者的盆底支持组织逐渐松弛形成脱垂。
5.载脂蛋白A-I参与PPAR信号通路,对组织纤维化和收缩能力产生影响,可能是POP的发生机制之一。
6.POP组血红蛋白表达较对照组显著减少,在一定程度上说明POP患者主骶韧带中血供减少。结合以往研究证实的绝经后女性生殖道血供减少,解释了绝经后女性易发生POP的临床现象。
●OBJECTIVES
1. To identify the differentially expressed proteins in cardinal-sacral ligament between patients with pelvic organ prolapsed (POP) and those without POP by2-D fluorescence difference gel electrophoresis (2-D DIGE) and mass spectrometry.
2. To further explore the possible molecular mechanism associated with POP based on the identified proteins.
●MATERIALS AND METHODS
1. Cardinal-sacral ligament samples were obtained from five postmenopausal patients with POP-Q stage Ⅲ and five age/BMI/parity matched postmenopausal patients without POP.
2. Total proteins were extracted and quantified, and then separated on two-dimensional gel, stained with silver with optimized experimental methods.
3. Samples were labeled with Cydye DIGE fluors and then separated by2D-DIGE. Gels were scanned and analyzed. Spots with average differential rate(|AV.Ratio|)≥1.5and P <0.05were identified as differentially expressed proteins.
4. Digested the picked spots and identified the peptides by MALDI-TOF-MS. Search the peptide mass fingerprint (PMF) in the database.
●RESULTS
1. High-quality proteins were extracted from the samples, and could be well separated in the2D gel. The mean detection rate was1224±22.
2. The image analysis showed that the average protein spots were1111±54in DIGE. A total of33differentially expressed proteins spots were detected between POP and normal patients, all of which were down-regulated in POP group. The most differentiated spot showed8.5fold down-regulation.
3. Twelve proteins were identified by MALDI-TOF-MS. They were serum albumin, fibrinogen, unnamed protein, electron transfer flavoprotein, hemoglobin, apolipoprotein A-I, actin, transgelin, cofilin-1, cyclophilin A, myosin and galectin-1respectively.
●CONCLUSIONS
1. Cardinal-sacral ligament proteins could be well extracted and purified by mechanical grinding, homogenization and ultrasonication. Proteins in this tissue could be well separated in24cm PH3-10non-liner gel.2-D DIGE can be used as a standard method to study the differentially expressed protein in POP.
2. Galectin-1and cyclophilin are essential factors for nerve regeneration. The down-regulation of these two proteins in POP group suggests that nerve injury contributes to the development of POP.
3. The defect of electron transfer flavoprotein relates to mitochondrial dysfunction. Mitochondrial dysfunction may aggravate the tissue aging of patients and increase the risk of POP.
4. Actin, transgelin, myosin and cofilin-1contribute to the cell skeleton and cell contraction. The lower expressions of these proteins in POP group relax the pelvic support tissues and lead to prolapse.
5. Apolipoprotein A-I (ApoAI) involves in PPAR pathway. The down-graduation of ApoA-I has significant effect on the development of tissue fibrosis and may weaken the performance of contraction. It may be a potential factor for development of POP.
6. Hemoglobin decrease in POP group suggests the reduction of blood supply in the patients' cardinal-sacral ligament. Decrease of hemoglobin in POP group is consistent with previous study, and suggests the reduction of blood supply might contribute to the development of POP too, explains that menopausal women are the high-risk group of
1.应用双向荧光差异凝胶电泳和质谱技术,建立绝经后POP患者与正常女性主骶韧带的蛋白质表达谱,筛选并鉴定POP患者与正常对照之间的差异表达蛋白。
2.分析差异表达蛋白,探讨POP发生的分子机制。
●材料和方法
1.在绝经状态、年龄、体重指数、产次等影响POP发生的重要因素匹配的前提下,选取5例POP与5例无POP患者的子宫主骶韧带复合体标本。
2.提取组织总蛋白,普通双向电泳分离,银染显色鉴定蛋白质抽提质量以及在胶图上的分布情况,并优化实验方法。
3.荧光染料分别标记POP组、对照组以及内标,进行双向电泳得到双向荧光差异凝胶图谱。同时制作制备胶。对胶图进行匹配和差异分析,筛选出两组之间|AV.Ratio|≥1.5,P<0.05的差异表达蛋白质点。
4.将差异蛋白质点胶内酶解后进行MALDI-TOF质谱分析和数据库搜索,鉴定差异表达的蛋白质点。
●实验结果
1.提取的组织蛋白经定量和普通双向电泳检测,蛋白质浓度符合实验要求,在胶图上分离情况满意,平均可获得1224±22个蛋白质点。
2.获得5张双向荧光差异凝胶电泳胶图,每张胶图上共约1111±54个蛋白质点,经过比较分析筛选出33个差异表达蛋白质点,均在POP组下调,最大下调比例为8.5倍。
3.质谱成功鉴定出12种蛋白,分别是白蛋白、纤维蛋白原、未知蛋白、电子传递黄素蛋白、血红蛋白、载脂蛋白A-I、肌动蛋白、转胶蛋白、丝切蛋白、亲环素A、肌球蛋白、半凝乳素-1。
●结论
1.经过机械研磨、匀浆以及超声破碎即可使韧带组织的提取蛋白质浓度和纯度基本满足实验要求,使用24cm PH3-10非线性胶条可以达到较为理想的蛋白质分离效果。双向电泳可作为筛选POP差异表达蛋白的研究方法。
2.半凝乳素-1和亲环素A在神经损伤修复中发挥重要作用。这两种蛋白在POP组的下调说明盆底神经损伤可能是POP发生的病因之一。
3.电子传递黄素蛋白的减少与线粒体异常相关,线粒体的异常可加重患者盆底组织的衰老程度,增加POP发生的风险。
4.肌动蛋白、转胶蛋白、肌球蛋白和丝切蛋白的下调可导致细胞骨架异常以及收缩功能异常,使POP患者的盆底支持组织逐渐松弛形成脱垂。
5.载脂蛋白A-I参与PPAR信号通路,对组织纤维化和收缩能力产生影响,可能是POP的发生机制之一。
6.POP组血红蛋白表达较对照组显著减少,在一定程度上说明POP患者主骶韧带中血供减少。结合以往研究证实的绝经后女性生殖道血供减少,解释了绝经后女性易发生POP的临床现象。
●OBJECTIVES
1. To identify the differentially expressed proteins in cardinal-sacral ligament between patients with pelvic organ prolapsed (POP) and those without POP by2-D fluorescence difference gel electrophoresis (2-D DIGE) and mass spectrometry.
2. To further explore the possible molecular mechanism associated with POP based on the identified proteins.
●MATERIALS AND METHODS
1. Cardinal-sacral ligament samples were obtained from five postmenopausal patients with POP-Q stage Ⅲ and five age/BMI/parity matched postmenopausal patients without POP.
2. Total proteins were extracted and quantified, and then separated on two-dimensional gel, stained with silver with optimized experimental methods.
3. Samples were labeled with Cydye DIGE fluors and then separated by2D-DIGE. Gels were scanned and analyzed. Spots with average differential rate(|AV.Ratio|)≥1.5and P <0.05were identified as differentially expressed proteins.
4. Digested the picked spots and identified the peptides by MALDI-TOF-MS. Search the peptide mass fingerprint (PMF) in the database.
●RESULTS
1. High-quality proteins were extracted from the samples, and could be well separated in the2D gel. The mean detection rate was1224±22.
2. The image analysis showed that the average protein spots were1111±54in DIGE. A total of33differentially expressed proteins spots were detected between POP and normal patients, all of which were down-regulated in POP group. The most differentiated spot showed8.5fold down-regulation.
3. Twelve proteins were identified by MALDI-TOF-MS. They were serum albumin, fibrinogen, unnamed protein, electron transfer flavoprotein, hemoglobin, apolipoprotein A-I, actin, transgelin, cofilin-1, cyclophilin A, myosin and galectin-1respectively.
●CONCLUSIONS
1. Cardinal-sacral ligament proteins could be well extracted and purified by mechanical grinding, homogenization and ultrasonication. Proteins in this tissue could be well separated in24cm PH3-10non-liner gel.2-D DIGE can be used as a standard method to study the differentially expressed protein in POP.
2. Galectin-1and cyclophilin are essential factors for nerve regeneration. The down-regulation of these two proteins in POP group suggests that nerve injury contributes to the development of POP.
3. The defect of electron transfer flavoprotein relates to mitochondrial dysfunction. Mitochondrial dysfunction may aggravate the tissue aging of patients and increase the risk of POP.
4. Actin, transgelin, myosin and cofilin-1contribute to the cell skeleton and cell contraction. The lower expressions of these proteins in POP group relax the pelvic support tissues and lead to prolapse.
5. Apolipoprotein A-I (ApoAI) involves in PPAR pathway. The down-graduation of ApoA-I has significant effect on the development of tissue fibrosis and may weaken the performance of contraction. It may be a potential factor for development of POP.
6. Hemoglobin decrease in POP group suggests the reduction of blood supply in the patients' cardinal-sacral ligament. Decrease of hemoglobin in POP group is consistent with previous study, and suggests the reduction of blood supply might contribute to the development of POP too, explains that menopausal women are the high-risk group of
引文
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1、Ghetti C, Lowder JL, Ellison R, et al. Depressive symptoms in women seeking surgery for pelvic organ prolapse. Int Urogynecol J Pelvic Floor Dysfunct,2010 Mar 24. [Epub ahead of print]
2、DeLancey JO. Anatomic aspects of vaginal eversion after hysterectomy. Am J Obstet Gynecol,1992, 166(6 Pt 1):1717-24.
3、Morley R, Cumming J, Weller R. Morphology and neuropathology of the pelvic floor in patients with stress incontinence. Int Urogynecol J Pelvic Floor Dysfunct,1996,7(1):3-12.
4、Hilliges M, Falconer C, Ekman-Ordeberg G, et al. Innervation of the human vaginal mucosa as revealed by PGP 9.5 immunohistochemistry. Acta Anat (Basel),1995,153(2):119-26.
5、蒋芳,朱兰,郎景和,等。盆底功能障碍性疾病患者阴道前后壁中蛋白基因产物9.5和血管活性肠肽的表达研究。生殖医学杂志,2008,17(6)：444-48.
6、陈娟,郎景和,朱兰,等。压力性尿失禁患者阴道黏膜的神经表达。中华妇产科杂志,2004,39(4),254-256.
7、海宁,朱兰,郎景和。盆底功能障碍性疾病患者会阴神经潜伏期测定在隐匿性压力性尿失禁诊断中的意义。中华妇产科杂志,2009,44(2)：145-147.
8、Deffieux X, Hubeaux K, Amarenco G. Female urinary stress incontinence:Analysis of pathophysiological hypothesis. J Gynecol Obstet Biol Reprod,2008,37(2):186-96.
9、Miller JM, Ashton-Miller JA, DeLancey JO. A pelvic muscle precontraction can reduce cough-related urine loss in selected. J Am Geriatr Soc,1998,46(7):870-74.
10、L Zhu, JH Lang, J Chen, et al. Morphologic study on levator ani muscle in patients with pelvic organ prolapse and stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct,2005,16:401-404.
11、Busacchi P, Perri T, Paradisi R, et al. Abnormalities of somatic peptide-containing nerves supplying the pelvic floor of women with genitourinary prolapse and stress urinary incontinence. Urology,2004, 63(3):591-95.
12、Gregory WT, Lou JS, Stuyvesant A, et al. Quantitative electromyography of the anal sphincter after uncomplicated vaginal delivery. Obstet Gynecol,2004,104(2):327-35.
13、Dietz HP. The aetiology of prolapse. Int Urogynecol J Pelvic Floor Dysfunct,2008,19(10):1323-29.
14、Takano CC, Girao MJ, Sartori MG, et al. Analysis of collagen in parametrium and vaginal apex of women with and without uterine prolapse. Int Urogynecol J Pelvic Floor Dysfunct,2002,13:342-345.
15、Wong MY, Harmanli OH, Agar M, et al. Collagen content of nonsupport tissue in pelvic organ prolapse and stress urinary incontinence. Am J Obstet Gynecol,2003,189:1597-99.
16、Goepel C, Hefler L, Methfessel HD, Koelbl H. Periurethral connective tissue status of postmenopausal women with genital prolapse with and without stress incontinence. Acta Obstet Gynecol Scand,2003,82:659-64.
17、Chen Y, Desautel M, Anderson A, et al. Collagen synthesis is not altered in women with stress urinary incontinence. Neurourol Urodyn,2004,23:367-73.
18、Kushner L, Mathrubuthan M, Burney T, et al. Excretion of collagen derived peptides is increased in women with stress urinary incontinence. Neurourol Urodyn,2004,23:198-203.
19、Lang J, Zhu L, Sun ZJ, et al. Clinical study on collagen and stress urinary incontinence. Clin Exp Obstet Gynecol,2002,29:180-82.
20、Moalli PA, Shand SH, Zyczynski HM, et al. Remodeling of vaginal connective tissue in patients with prolapse. Obstet Gynecol,2005,106:953-963.
21、Ewies AA, Al-Azzawi F, Thompson J. Changes in extracellular matrix proteins in the cardinal ligaments of postmenopausal women with or without prolapse:a computerized immunohistomorphometric analysis. Hum Reprod,2003,18:2189-95.
22、Moalli PA, Talarico LC, Sung VW, et al. Impact of menopause on collagen subtypes in the arcus tendineous fasciae pelvis. Am J Obstet Gynecol,2004,190:620-27.
23、Jackson SR, Avery NC, Tarlton JF, et al. Changes in metabolism of collagen in genitourinary prolapse. Lancet,1996,347:1658-61.
24、Boreham MK, Zaretsky MV, Corton MM, et al. Appearance of the levator ani muscle in pregnancy as assessed by 3-D MRI. Am J Obstet Gynecol,2005,193:2159-64.
25、Mant J, Painter R, Vessey M. Epidemiology of genital prolapse:observations from the Oxford Family Planning Association study. Br J Obstet Gynaecol,1997,104:579-85.
26、Dannecker C, Lienemann A, Fischer J, et al. Influence of spontaneous and instrumental vaginal delivery on objective measures of pelvic organ support assessment with the pelvic organ prolapse quantification (POP-Q) technique and functional cine magnetic resonance imaging. Eur J Obstet Gynecol Reprod Biol,2004,115(l):32-38.
27、Mott JD, Werb Z. Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol, 2004,16:558-64.
28、Chen B, Wen Y, Zhang Z, et al. Menstrual phase-dependent gene expression differences in periurethral vaginal tissue from women with stress incontinence. Am J Obstet Gynecol,2003, 189:89-97.
29、Mietz H, Chevez-Barrios P, Lieberman MW, et al. Decorin and suramin inhibit ocular fibroblast collagen production. Graefes Arch Clin Exp Ophthalmol,1997,235:399-403.
30、Kobak W, Lu J, Hardart A, et al. Expression of lysyl oxidase and transforming growth factor beta2 in women with severe pelvic organ prolapse. J Reprod Med,2005,50:827-31.
31、Swift SE. The distribution of pelvic organ support in a population of female subjects seen for routine gynecologic health care. Am J Obstet Gynecol,2000,183(2):277-85.
32、Drewes PG, Yanagisawa H, Starcher B, et al. Pelvic organ prolapse in fibulin-5 knockout mice: pregnancy-induced changes in elastic fiber homeostasis in mouse vagina. Am J Pathol,2007, 170:578-89.
33、Rizk DE, Hassan HA, Al Marzouqi AH, et al. Combined estrogen and ghrelin administration restores number of blood vessels and collagen type Ⅰ/Ⅲ ratio in the urethral and anal canal submucosa of old ovariectomized rats. Int Urogynecol J Pelvic Floor Dysfunct,2008,19:547-52.
34、Jackson S, James M, Abrams P. The effect of oestradiol on vaginal collagen metabolism in postmenopausal women with genuine stress incontinence. Br J Obstet Gynaecol,2002,109:339-44.
35、Baden WF, Walker TA. Genesis of the vaginal profile:a correlated classification of vaginal relaxation. Clin Obstet Gynecol,1972,15(4):1048-54.
36、Lang JH, Zhu L, Sun ZJ, et al. Estrogen levels and estrogen receptors in patients with stress urinary incontinence and pelvic organ prolapse. Int J Gynaecol Obstet,2003,80:35-39.
37、Ewies AA, Thompson J, Al Azzawi F. Changes in gonadal steroid receptors in the cardinal ligaments of prolapsed uteri:immunohistomorphometric data. Hum Reprod,2004,19:1622-1628.
38、Wasinger V C, Cordewell S J, Cerpa-Poljak A, et al. Progress with gene-product mapping of the Mollicutes:Mycoplasma genitalium. Electrophoresis.1995,16:1090-1094.
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1、Ghetti C, Lowder JL, Ellison R, et al. Depressive symptoms in women seeking surgery for pelvic organ prolapse. Int Urogynecol J Pelvic Floor Dysfunct,2010 Mar 24. [Epub ahead of print]
2、DeLancey JO. Anatomic aspects of vaginal eversion after hysterectomy. Am J Obstet Gynecol,1992, 166(6 Pt 1):1717-24.
3、Morley R, Cumming J, Weller R. Morphology and neuropathology of the pelvic floor in patients with stress incontinence. Int Urogynecol J Pelvic Floor Dysfunct,1996,7(1):3-12.
4、Hilliges M, Falconer C, Ekman-Ordeberg G, et al. Innervation of the human vaginal mucosa as revealed by PGP 9.5 immunohistochemistry. Acta Anat (Basel),1995,153(2):119-26.
5、蒋芳,朱兰,郎景和,等。盆底功能障碍性疾病患者阴道前后壁中蛋白基因产物9.5和血管活性肠肽的表达研究。生殖医学杂志,2008,17(6)：444-48.
6、陈娟,郎景和,朱兰,等。压力性尿失禁患者阴道黏膜的神经表达。中华妇产科杂志,2004,39(4),254-256.
7、海宁,朱兰,郎景和。盆底功能障碍性疾病患者会阴神经潜伏期测定在隐匿性压力性尿失禁诊断中的意义。中华妇产科杂志,2009,44(2)：145-147.
8、Deffieux X, Hubeaux K, Amarenco G. Female urinary stress incontinence:Analysis of pathophysiological hypothesis. J Gynecol Obstet Biol Reprod,2008,37(2):186-96.
9、Miller JM, Ashton-Miller JA, DeLancey JO. A pelvic muscle precontraction can reduce cough-related urine loss in selected. J Am Geriatr Soc,1998,46(7):870-74.
10、L Zhu, JH Lang, J Chen, et al. Morphologic study on levator ani muscle in patients with pelvic organ prolapse and stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct,2005,16:401-404.
11、Busacchi P, Perri T, Paradisi R, et al. Abnormalities of somatic peptide-containing nerves supplying the pelvic floor of women with genitourinary prolapse and stress urinary incontinence. Urology,2004, 63(3):591-95.
12、Gregory WT, Lou JS, Stuyvesant A, et al. Quantitative electromyography of the anal sphincter after uncomplicated vaginal delivery. Obstet Gynecol,2004,104(2):327-35.
13、Dietz HP. The aetiology of prolapse. Int Urogynecol J Pelvic Floor Dysfunct,2008,19(10):1323-29.
14、Takano CC, Girao MJ, Sartori MG, et al. Analysis of collagen in parametrium and vaginal apex of women with and without uterine prolapse. Int Urogynecol J Pelvic Floor Dysfunct,2002,13:342-345.
15、Wong MY, Harmanli OH, Agar M, et al. Collagen content of nonsupport tissue in pelvic organ prolapse and stress urinary incontinence. Am J Obstet Gynecol,2003,189:1597-99.
16、Goepel C, Hefler L, Methfessel HD, Koelbl H. Periurethral connective tissue status of postmenopausal women with genital prolapse with and without stress incontinence. Acta Obstet Gynecol Scand,2003,82:659-64.
17、Chen Y, Desautel M, Anderson A, et al. Collagen synthesis is not altered in women with stress urinary incontinence. Neurourol Urodyn,2004,23:367-73.
18、Kushner L, Mathrubuthan M, Burney T, et al. Excretion of collagen derived peptides is increased in women with stress urinary incontinence. Neurourol Urodyn,2004,23:198-203.
19、Lang J, Zhu L, Sun ZJ, et al. Clinical study on collagen and stress urinary incontinence. Clin Exp Obstet Gynecol,2002,29:180-82.
20、Moalli PA, Shand SH, Zyczynski HM, et al. Remodeling of vaginal connective tissue in patients with prolapse. Obstet Gynecol,2005,106:953-963.
21、Ewies AA, Al-Azzawi F, Thompson J. Changes in extracellular matrix proteins in the cardinal ligaments of postmenopausal women with or without prolapse:a computerized immunohistomorphometric analysis. Hum Reprod,2003,18:2189-95.
22、Moalli PA, Talarico LC, Sung VW, et al. Impact of menopause on collagen subtypes in the arcus tendineous fasciae pelvis. Am J Obstet Gynecol,2004,190:620-27.
23、Jackson SR, Avery NC, Tarlton JF, et al. Changes in metabolism of collagen in genitourinary prolapse. Lancet,1996,347:1658-61.
24、Boreham MK, Zaretsky MV, Corton MM, et al. Appearance of the levator ani muscle in pregnancy as assessed by 3-D MRI. Am J Obstet Gynecol,2005,193:2159-64.
25、Mant J, Painter R, Vessey M. Epidemiology of genital prolapse:observations from the Oxford Family Planning Association study. Br J Obstet Gynaecol,1997,104:579-85.
26、Dannecker C, Lienemann A, Fischer J, et al. Influence of spontaneous and instrumental vaginal delivery on objective measures of pelvic organ support assessment with the pelvic organ prolapse quantification (POP-Q) technique and functional cine magnetic resonance imaging. Eur J Obstet Gynecol Reprod Biol,2004,115(l):32-38.
27、Mott JD, Werb Z. Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol, 2004,16:558-64.
28、Chen B, Wen Y, Zhang Z, et al. Menstrual phase-dependent gene expression differences in periurethral vaginal tissue from women with stress incontinence. Am J Obstet Gynecol,2003, 189:89-97.
29、Mietz H, Chevez-Barrios P, Lieberman MW, et al. Decorin and suramin inhibit ocular fibroblast collagen production. Graefes Arch Clin Exp Ophthalmol,1997,235:399-403.
30、Kobak W, Lu J, Hardart A, et al. Expression of lysyl oxidase and transforming growth factor beta2 in women with severe pelvic organ prolapse. J Reprod Med,2005,50:827-31.
31、Swift SE. The distribution of pelvic organ support in a population of female subjects seen for routine gynecologic health care. Am J Obstet Gynecol,2000,183(2):277-85.
32、Drewes PG, Yanagisawa H, Starcher B, et al. Pelvic organ prolapse in fibulin-5 knockout mice: pregnancy-induced changes in elastic fiber homeostasis in mouse vagina. Am J Pathol,2007, 170:578-89.
33、Rizk DE, Hassan HA, Al Marzouqi AH, et al. Combined estrogen and ghrelin administration restores number of blood vessels and collagen type Ⅰ/Ⅲ ratio in the urethral and anal canal submucosa of old ovariectomized rats. Int Urogynecol J Pelvic Floor Dysfunct,2008,19:547-52.
34、Jackson S, James M, Abrams P. The effect of oestradiol on vaginal collagen metabolism in postmenopausal women with genuine stress incontinence. Br J Obstet Gynaecol,2002,109:339-44.
35、Baden WF, Walker TA. Genesis of the vaginal profile:a correlated classification of vaginal relaxation. Clin Obstet Gynecol,1972,15(4):1048-54.
36、Lang JH, Zhu L, Sun ZJ, et al. Estrogen levels and estrogen receptors in patients with stress urinary incontinence and pelvic organ prolapse. Int J Gynaecol Obstet,2003,80:35-39.
37、Ewies AA, Thompson J, Al Azzawi F. Changes in gonadal steroid receptors in the cardinal ligaments of prolapsed uteri:immunohistomorphometric data. Hum Reprod,2004,19:1622-1628.
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