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v Integrin and -Actin Genes through Cytoskeletally-Based Mechanotransduction Mechanisms in Bladder Smooth Muscle Cells
1 Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA, USA
2 Department of Dermatology, Thomas Jefferson University, Philadelphia, PA, USA
3 Department of Anatomy and Cell Biology, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, USA
* To whom correspondence should be addressed. E-mail: brahim.chaqour{at}downstate.edu.
Application of cyclic strain to bladder smooth muscle (SM) cells results in profound alterations of the histo-morphometry, phenotype and function of the cells. The onset of this process is characterized by the activation of a cascade of signaling events coupled to progressive and perhaps, interdependent changes of gene expression. In particular, externally applied cyclic stretch to cultured
bladder SM cells results in the transient expression of the Cyr61 gene that encodes a cysteine-rich heparin-binding protein originally described as a proangiogenic factor capable of altering the gene programs for angiogenesis, adhesion and extracellular matrix synthesis. In this study, we investigated the effects of mechanical stretch-induced Cyr61 on the expression of potential
mechano-sensitive Cyr61 target genes and the signaling pathways involved. We showed that suppression of Cyr61 expression with an adenoviral vector encoding an anti-sense oligonucleotide reduced mechanical strain-induced VEGF, 
v integrin and SM -actin gene expression but had no effect on myosin heavy chain (MHC) isoforms, SM-1 and SM-2. Signaling pathways involving RhoA GTPase, phosphatidyl inositol 3-kinase and cytoskeletal actin dynamics altered stretchinduced
Cyr61 and Cyr61 target genes. Reciprocally, adenovirus-mediated overexpression of Cyr61 in cells cultured under static conditions increased the expression of VEGF, v integrin and SM -
actin, as well as that of SM-1 and SM-2 isoforms suggesting that the effects of a sustained expression of Cyr61 extend to SM specific contractile function. These effects were dependent on integrity of the actin cytoskeleton. Together, these results indicate that Cyr61 is an important determinant of the genetic reprogramming that occurs in mechanically challenged cells.
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