Loss of the Mechanotransducer Zyxin Promotes a Synthetic Phenotype of Vascular Smooth Muscle Cells

Abstract

BackgroundExposure of vascular smooth muscle cells (VSMCs) 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 VSMCs, 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 VSMCs at the cellular level might thus offer a better mechanistic insight. We aimed to characterize zyxin-dependent changes in gene expression in VSMCs exposed to biomechanical stretch and define the functional role of zyxin in controlling the resultant VSMC phenotype.Methods and ResultsDNA microarray analysis was used to identify genes and pathways that were zyxin regulated in static and stretched human umbilical artery–derived and mouse aortic VSMCs. Zyxin-null VSMCs 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 VSMCs, and a condensed and localized accumulation of F-actin upon stretch.ConclusionsAt the cellular level, zyxin is a key regulator of stretch-induced gene expression. Loss of zyxin drives VSMCs toward a synthetic phenotype, a process further consolidated by exaggerated stretch.

Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow‐ and pressure‐induced arterial remodeling in mice

“…The consequent load exerted on the cytoskeleton evokes intracellular signaling, as proposed by the model of tensegrity (32). Recording of biomechanical forces is conducted by molecular sensors, including integrins (33), focal adhesion proteins (34), ion channels, such as transient receptor potential channels (35), and GPCR (36). The corresponding signaling cascades converge to modify the activity of transcription factors that ultimately (re)define the cellular phenotype.…”

Stretch-induced actomyosin contraction in epithelial tubes: Mechanotransduction pathways for tubular homeostasis

“…In vivo , zyxin is not essential for mechanotransduction, as zyxin null mice are viable [46]. However, vascular smooth muscle cells from zyxin null mice show reduced contractility with a poorly organized actin network [47]. …”

Proteomic analysis of differentially expressed proteins in endothelial cells under low shear stress

“…Mechanisms by which zyxin affects gene expression have been proposed [20] and this protein is a potential therapeutic target to impact the onset of endothelial cell phenotype. Zyxin is usually associated with focal adhesions and stress bers, and plays major role in stretch-induced endothelial gene expression [21,22]. Mechanical forces mobilize zyxin from focal adhesions to actin laments and regulate cytoskeletal reinforcement [23].…”