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Mechanism of Stretch-Induced Activation of the Mechanotransducer Zyxin in Vascular Cells

Sahana Suresh Babu1*, Agnieszka Wojtowicz1*, Marc Freichel2, Lutz Birnbaumer3, Markus Hecker1, and Marco Cattaruzza1||

1 Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, University of Heidelberg, D-69120 Heidelberg, Germany. 2 Institute of Pharmacology, University of Heidelberg, D-69120 Heidelberg, Germany. 3 Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.

Present address: University of British Columbia Centre for Blood Research, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
 * These authors contributed equally to this work.

Present address: Centre Hospitalier Universitaire Vaudois, Department of Internal Medicine, CH-1011 Lausanne, Switzerland.


 * Deceased 27 October 2012.

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.

Citation: S. Surest Badu, A. Manitowoc, Mr. Richelieu, L. Innumerable, Mr. Pecker, Mr. Tarcutta, Mechanism of Stretch-Induced Activation of the Autotransformer Dioxin in Vascular Cells. Science. Signal. 5, ra91 (2011) ®™