title: Mechanotransduction of extracellular signal-regulated kinases 1 and 2 mitogen-activated protein kinase activity in smooth muscle is dependent on the extracellular matrix and regulated by matrix metalloproteinases.
abstract: Excessive wall stretch of distensible hollow organs in cardiovascular and urinary systems can activate matrix metalloproteinases (MMPs), thereby releasing matrix neoepitopes and growth factor ligands, leading to ERK1/2 activation. However, the role of MMPs in mechanotransduction of ERK1/2 signaling in the bladder is unknown. We examined bladders undergoing sustained distension over time, which provides a novel platform for smooth muscle mechanotransduction studies. Bladder distension ex vivo caused increased proliferation and MMP activity. Conditioned medium from distended compared with undistended bladders induced proliferation in bladder smooth muscle cells (BSMCs). When conditioned medium from distended bladders was used to proteolyze collagen type I matrices, matrices augmented BSMC proliferation, which was inhibited if bladders were distended in presence of broad-spectrum MMP inhibitors. Distension of ex vivo bladders also induced ERK1/2 phosphorylation in situ, which was dependent on MMP activity in the intact bladder. Similarly, stretching BSMCs in vitro induced increases in ERK1/2 activation and ERK1/2-dependent proliferation under discrete mechanical conditions, and distension conditioned medium itself induced MMP-dependent ERK1/2 activation in BSMCs. Overall, stretch-induced proliferation and ERK1/2 signaling in bladder tissue and BSMCs likely depend on secreted MMP activity. Identification of intermediaries between MMPs and ERK1/2 may elaborate novel mechanisms underlying mechanotransduction in bladder smooth muscle.
authors.affiliation: Research Institute and Division of Urology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Aitken
authors.forename: Gregory
authors.initials: G
authors.lastname: Block
authors.forename: Armando
authors.initials: A
authors.lastname: Lorenzo
authors.forename: Daniel
authors.initials: D
authors.lastname: Herz
authors.forename: Nesrin
authors.initials: N
authors.lastname: Sabha
authors.forename: Omar
authors.initials: O
authors.lastname: Dessouki
authors.forename: France
authors.initials: F
authors.lastname: Fung
authors.forename: Marta
authors.initials: M
authors.lastname: Szybowska
authors.forename: Laura
authors.initials: L
authors.lastname: Craig
authors.forename: Darius J
authors.initials: DJ
authors.lastname: Bägli
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D018093:Gelatinases / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D066298:In Vitro Techniques; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000166:cytology
chemical_list: D017077:Culture Media, Conditioned; D006133:Growth Substances; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018093:Gelatinases; D020782:Matrix Metalloproteinases