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1 The Urological Diseases Research Center, Department of Urology, Children's Hospital Boston and Harvard Medical School, Boston, MA, USA
2 Department of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA, USA
3 Department of Ophthalmology, Children's Hospital Boston and Harvard Medical School, Boston, MA, USA
4 Division of Infection, Immunity and Repair Research, Department of Surgery, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: Rosalyn.adam{at}childrens.harvard.edu.
Application of mechanical stimuli has been shown to alter gene expression in bladder smooth muscle cells (SMC). To date only a limited number of "stretchresponsive" genes in this cell type have been reported. We employed oligonucleotide arrays to identify stretch-sensitive genes in primary culture human bladder SMC subjected to repetitive mechanical stimulation for 4 h. Differential gene expression between stretched and non-stretched cells was assessed using Significance Analysis of Microarrays (SAM). Expression of twenty out of 11,731 expressed genes (~0.17%) was altered >2-fold following stretch, with 19 genes induced and one gene (FGF-9) repressed. Using real-time RT-PCR, we tested independently the responsiveness of 15 genes to stretch and to platelet-derived growth factor-BB (PDGF-BB), another hypertrophic stimulus for bladder SMC. In response to both stimuli, expression of 13 genes increased, one gene (FGF-9) decreased, and one gene was unchanged. Six transcripts (HB-EGF, BMP-2, COX-2, LIF, PAR-2, and FGF-9) were evaluated using an ex vivo rat model of bladder distension. HB-EGF, BMP-2, COX-2, LIF and PAR-2 increased with bladder stretch ex vivo, whereas FGF-9 decreased, consistent with expression changes observed in vitro. In silico analysis of microarray data using the FIRED algorithm identified c-jun, AP-1, ATF-2 and neurofibromin-1 (NF-1) as potential transcriptional mediators of stretch signals. Furthermore, the promoters of nine out of 13 stretch-responsive genes contained AP-1 binding sites. These observations identify stretch as a highly selective regulator of gene expression in bladder SMC. Moreover, they suggest that mechanical and growth factor signals converge on common transcriptional regulators that include members of the AP-1 family.
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