Cyr61 mediates the expression of VEGF, alphav-integrin, and alpha-actin genes through cytoskeletally based mechanotransduction mechanisms in bladder smooth muscle cells.
Application of cyclic strain to bladder smooth muscle (SM) cells results in profound alterations of the histomorphometry, 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 mechanosensitive Cyr61 target genes and the signaling pathways involved. We showed that suppression of Cyr61 expression with an adenoviral vector encoding an antisense oligonucleotide reduced mechanical strain-induced VEGF, alpha(v)-integrin, and SM alpha-actin gene expression but had no effect on the myosin heavy chain isoforms SM-1 and SM-2. Signaling pathways involving RhoA GTPase, phosphatidyl inositol 3-kinase, and cytoskeletal actin dynamics altered stretch-induced Cyr61 and Cyr61 target genes. Reciprocally, adenovirus-mediated overexpression of Cyr61 in cells cultured under static conditions increased the expression of VEGF, alpha(v)-integrin, and SM alpha-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.
Zhou
Dongming
D
Dept. of Anatomy and Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Ave., Box 5, Brooklyn, NY 11203-2098, USA.
Herrick
David J
DJ
Rosenbloom
Joel
J
Chaqour
Brahim
B
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000378:metabolism*; D039564:Integrin alphaV / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D010812:Physical Stimulation / Q000379:methods; D013314:Stress, Mechanical; D001743:Urinary Bladder / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D000199:Actins; D017874:Immediate-Early Proteins; D039564:Integrin alphaV; D036341:Intercellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A