Mol. Hum. Reprod. Advance Access originally published online on January 9, 2008
Molecular Human Reproduction 2008 14(2):127-135; 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 estradiol and levormeloxifene
1Department of Gynaecology, The Ipswich Hospital, Ipswich, UK 2Gynaecology Research Unit, University Hospitals of Leicester, Leicester, UK 3Department of Medicine, Leicester University, Leicester, UK 4Department of Epidemiology, Leicester University, Leicester, UK 5MRC Molecular Endocrinology Group, Leicester University, Leicester, UK
6 Correspondence address. Tel: +44-116-258-7506; Fax: +44-116-258-6098; 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 remodelling, 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 estradiol (E2) on the cytoskeleton of cultured fibroblasts. The percentage of cells with abnormal F-actin configuration was significantly higher in fibroblasts subjected to stretch compared with the static model (P < 0.0001). Levormeloxifene caused similar significant alterations in actin morphology of the static fibroblasts. The use of E2 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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