Mol. Hum. Reprod. Advance Access published online on January 9, 2008
Molecular Human Reproduction, doi:10.1093/molehr/gam090
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Changes in transcription profile and cytoskeleton morphology in pelvic ligament fibroblasts in response to stretch - the effects of oestradiol and levormeloxifene
1Consultant in Obstetrics and Gynaecology, The Ipswich Hospital 2Clinical Research Fellow, Gynaecology Research Unit, University Hospitals of Leicester. 3Postdoctoral Research Fellow, Gynaecology Research Unit, University Hospitals of Leicester. 4Clinical lecturer in Medicine, Leicester University. 5Professor of Epidemiology, Leicester University. 6Postdoctoral Research Fellow, MRC Molecular Endocrinology Group, Leicester University 7Honorary Reader, MRC Molecular Endocrinology Group, Leicester University. 8Consultant Gynaecologist, Gynaecology Research Unit, University Hospitals of Leicester, UK
Corresponding author: Farook Al-Azzawi Address: Gynaecology Research Unit, University Hospitals of Leicester Victoria Building, Leicester LE1 5WW Tel.: 0116 258 7506 Fax: 0116 258 6098 E-mail: farookalazzawi{at}yahoo.co.uk
Failure of ligamentous support of the genital tract to resist intra-abdominal pressure is a plausible underlying mechanism for the development of pelvic organ prolapse, but the nature of the molecular response of pelvic tissue support remains unknown. We hypothesized that the expression of genes coding for proteins involved in maintaining the cellular and extracellular integrity would be altered as a result of mechanical stretch. Therefore, cDNA microarrays were used to examine the difference in transcriptional profile in RNA of primary culture fibroblasts subjected to mechanical stretch and those that remained static. Out of 34 mechano-responsive genes identified (P<0.05), four were coding for regulation of actin cytoskeleton remodeling, and its interaction with the extracellular matrix proteins; these are phosphatidyl inositol-4-phosphate 5-kinase (PIP5K1C), the human signal-induced proliferation associated gene-1 (SIPA-1), TNFRSF1A-associated via death domain (TRADD) and deoxyribonuclease 1-like 1 (DNase 1-L1). The transcriptosomal changes led us to investigate the phenotypic consequences of stretch, levormeloxifene and oestradiol on the cytoskeleton of cultured fibroblasts. The percentage of cells with abnormal F actin configuration was significantly higher in fibroblasts subjected to stretch compared to the static model (p<0.0001). Levormeloxifene caused similar significant alterations in actin morphology of the static fibroblasts. The use of oestradiol did not reverse the process or protect the cells from the effect of stretch, but significantly increased the rate of fibroblast proliferation, suggestive of a role in healing process. Mechanical stretch and/or levormeloxifene disturb the fibroblasts ability to maintain the cytoskeleton architecture and we speculate that they may disrupt ligamentous integrity and result in clinical prolapse.
Key Words: Actin/Levormeloxifene/Stretch/Microarray/Prolapse
Submitted on September 27, 2007; resubmitted on November 5, 2007; accepted on November 26, 2007.
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  S.S. Brizzolara, J. Killeen, and J. Urschitz Gene expression profile in pelvic organ prolapse Mol. Hum. Reprod., January 1, 2009; 15(1): 59 - 67. [Abstract] [Full Text] [PDF]
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