Mechanical stretch is a highly selective regulator of gene expression in human bladder smooth muscle cells

Rosalyn M. Adam, Samuel H. Eaton, Carlos Estrada, Ashish Nimgaonkar, Shu Ching Shih, Lois E H Smith, Isaac S. Kohane, Darius Bägli, Michael R. Freeman

Research output: Contribution to journalArticle

Abstract

Application of mechanical stimuli has been shown to alter gene expression in bladder smooth muscle cells (SMC). To date, only a limited number of "stretch-responsive" 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 nonstretched cells was assessed using Significance Analysis of Microarrays (SAM). Expression of 20 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, 1 gene (FGF-9) decreased, and 1 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 9 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.

Original languageEnglish (US)
Pages (from-to)36-44
Number of pages9
JournalPhysiological Genomics
Volume20
DOIs
StatePublished - Apr 2005
Externally publishedYes

Fingerprint

Regulator Genes
Smooth Muscle Myocytes
Urinary Bladder
Gene Expression
Genes
Transcription Factor AP-1
Microarray Analysis
Neurofibromin 1
Fibroblast Growth Factor 1
Fibroblast Growth Factor 2
Oligonucleotide Array Sequence Analysis
Computer Simulation
Real-Time Polymerase Chain Reaction
Intercellular Signaling Peptides and Proteins
Binding Sites

Keywords

  • Oligonucleotide array
  • Platelet-derived growth factor
  • Smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Mechanical stretch is a highly selective regulator of gene expression in human bladder smooth muscle cells. / Adam, Rosalyn M.; Eaton, Samuel H.; Estrada, Carlos; Nimgaonkar, Ashish; Shih, Shu Ching; Smith, Lois E H; Kohane, Isaac S.; Bägli, Darius; Freeman, Michael R.

In: Physiological Genomics, Vol. 20, 04.2005, p. 36-44.

Research output: Contribution to journalArticle

Adam, Rosalyn M. ; Eaton, Samuel H. ; Estrada, Carlos ; Nimgaonkar, Ashish ; Shih, Shu Ching ; Smith, Lois E H ; Kohane, Isaac S. ; Bägli, Darius ; Freeman, Michael R. / Mechanical stretch is a highly selective regulator of gene expression in human bladder smooth muscle cells. In: Physiological Genomics. 2005 ; Vol. 20. pp. 36-44.
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AU - Adam, Rosalyn M.

AU - Eaton, Samuel H.

AU - Estrada, Carlos

AU - Nimgaonkar, Ashish

AU - Shih, Shu Ching

AU - Smith, Lois E H

AU - Kohane, Isaac S.

AU - Bägli, Darius

AU - Freeman, Michael R.

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AB - Application of mechanical stimuli has been shown to alter gene expression in bladder smooth muscle cells (SMC). To date, only a limited number of "stretch-responsive" 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 nonstretched cells was assessed using Significance Analysis of Microarrays (SAM). Expression of 20 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, 1 gene (FGF-9) decreased, and 1 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 9 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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