Open AccessLoss of the Mechanotransducer Zyxin Promotes a Synthetic Phenotype of Vascular Smooth Muscle Cells
Author(s) -
Ghosh Subhajit,
Kollar Branislav,
Nahar Taslima,
Suresh Babu Sahana,
Wojtowicz Agnieszka,
Sticht Carsten,
Gretz Norbert,
Wagner Andreas H.,
Korff Thomas,
Hecker Markus
Publication year - 2015
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.114.001712
Subject(s) - phenotype , microbiology and biotechnology , vascular smooth muscle , myocardin , biology , focal adhesion , lim domain , rhoa , gene expression , transcription factor , gene , signal transduction , serum response factor , genetics , zinc finger , endocrinology , smooth muscle
Background Exposure of vascular smooth muscle cells ( VSMC s) to excessive cyclic stretch such as in hypertension causes a shift in their phenotype. The focal adhesion protein zyxin can transduce such biomechanical stimuli to the nucleus of both endothelial cells and VSMC s, albeit with different thresholds and kinetics. However, there is no distinct vascular phenotype in young zyxin‐deficient mice, possibly due to functional redundancy among other gene products belonging to the zyxin family. Analyzing zyxin function in VSMC s at the cellular level might thus offer a better mechanistic insight. We aimed to characterize zyxin‐dependent changes in gene expression in VSMC s exposed to biomechanical stretch and define the functional role of zyxin in controlling the resultant VSMC phenotype. Methods and Results DNA microarray analysis was used to identify genes and pathways that were zyxin regulated in static and stretched human umbilical artery–derived and mouse aortic VSMC s. Zyxin‐null VSMC s showed a remarkable shift to a growth‐promoting, less apoptotic, promigratory and poorly contractile phenotype with ≈90% of the stretch‐responsive genes being zyxin dependent. Interestingly, zyxin‐null cells already seemed primed for such a synthetic phenotype, with mechanical stretch further accentuating it. This could be accounted for by higher RhoA activity and myocardin‐related transcription factor‐A mainly localized to the nucleus of zyxin‐null VSMC s, and a condensed and localized accumulation of F‐actin upon stretch. Conclusions At the cellular level, zyxin is a key regulator of stretch‐induced gene expression. Loss of zyxin drives VSMC s toward a synthetic phenotype, a process further consolidated by exaggerated stretch.