title: Mechanism of stretch-induced activation of the mechanotransducer zyxin in vascular cells.
abstract: Vascular cells respond to supraphysiological amounts of stretch with a characteristic phenotypic change that results in dysfunctional remodeling of the affected arteries. Although the pathophysiological consequences of stretch-induced signaling are well characterized, the mechanism of mechanotransduction is unclear. We focused on the mechanotransducer zyxin, which translocates to the nucleus to drive gene expression in response to stretch. In cultured human endothelial cells and perfused femoral arteries isolated from wild-type and several knockout mouse strains, we characterized a multistep signaling pathway whereby stretch led to a transient receptor potential channel 3-mediated release of the endothelial vasoconstrictor peptide endothelin-1 (ET-1). ET-1, through autocrine activation of its B-type receptor, elicited the release of pro-atrial natriuretic peptide (ANP), which caused the autocrine activation of the ANP receptor guanylyl cyclase A (GC-A). Activation of GC-A, in turn, led to protein kinase G-mediated phosphorylation of zyxin at serine 142, thereby triggering the translocation of zyxin to the nucleus, where it was required for stretch-induced gene expression. Thus, we have identified a stretch-induced signaling pathway in vascular cells that leads to the activation of zyxin, a cytoskeletal protein specifically involved in transducing mechanical stimuli.
authors.affiliation: Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Sahana
authors.initials: S
authors.lastname: Suresh Babu
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wojtowicz
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
authors.forename: Marco
authors.initials: M
authors.lastname: Cattaruzza
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001158:Arteries / Q000166:cytology*; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D013314:Stress, Mechanical; D050051:Transient Receptor Potential Channels / Q000378:metabolism; D060589:Zyxin / Q000378:metabolism* / Q000502:physiology
chemical_list: D019332:Endothelin-1; D050051:Transient Receptor Potential Channels; C092842:ZYX protein, human; D060589:Zyxin; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase