Focal Adhesion Protein Zyxin Is a Mechanosensitive Modulator of Gene Expression in Vascular Smooth Muscle Cells

Abstract

Abstract-Excessive deformation of vascular smooth muscle cells (SMCs) caused by a prolonged increase in blood pressure (eg, in hypertension) results in an adaptive remodeling of the vessel wall that is characterized by SMC hypertrophy or hyperplasia and contributes to fixation of the increase in blood pressure. The onset of this process is characterized by a unique change in gene expression in the SMC. However, thus far, no transcription factor has been identified that specifically mediates mechanosensitive gene expression in these cells. Therefore, the role of a putative mechanotransducer, the cytoskeletal protein zyxin, was investigated in rat aortic cultured SMCs. Immunofluorescence and Western blot analysis revealed that on exposure to cyclic stretch, but not to osmotic stress or treatment with proinflammatory cytokines, zyxin dissociates from focal adhesions and accumulates in the nucleus. Unlike zyxin, vinculin, another focal adhesion-associated protein, did not translocate. Moreover, antisense oligonucleotide downregulation of zyxin protein abundance suggested that zyxin accumulation in the nucleus is a prerequisite for mechanosensitive gene expression in these cells. Thus, stretch-induced endothelin B receptor expression, for example, was attenuated, whereas that of tenascin-C was augmented after zyxin suppression. The data are consistent with a role for zyxin in transducing mechanical stimuli from the cell membrane to the nucleus in vascular SMCs and in controlling the expression of mechanosensitive genes that have been implicated in hypertension-induced arterial remodeling. y virtue of the resulting changes in circumferential wall stress and the degree of stretch that the cells are exposed to, blood pressure variations have a major impact on the phenotype of smooth muscle cells (SMCs) in conduit and resistance-size arteries. Although transient increases in blood pressure result in a compensatory increase in SMC tone, as exemplified by the myogenic response, pressure overload triggers a profound change in gene expression in these cells that ultimately leads to an adaptive remodeling of the vessel wall. 1 This is characterized by SMC hypertrophy (conduit arteries) or SMC hyperplasia (resistance-size arteries), resulting in an increase in wall thickness that offsets the blood pressure-induced rise in wall stress. However, this structural adaptation causes an increase in vascular resistance and, although aimed at regaining local blood flow control, eventually contributes to fixation of the elevated blood pressure as, eg, in hypertension. 2 Arterial hypertension is one of the primary risk factors for atherosclerosis, hence myocardial infarction, stroke, and dilated cardiomyopathy. Therefore, pressure-dependent arterial remodeling is a major contributor to the pathogenesis of these diseases. 3 Although the aforementioned interrelation is well established in the clinic, little is known about SMC mechanotransduction, namely the activation of transcription factors that specifically link deformation of the cell ...

Overexpression of LASP-1 mediates migration and proliferation of human ovarian cancer cells and influences zyxin localisation

“…Silencing of zyxin in HeLa cells resulted in significantly reduced actin stress fibres (Griffith et al, 2005), whereas under cyclic stretch zyxin only dissociated from focal contacts and accumulated in the nucleus, without affecting vinculin or actin filaments (Cattaruzza et al, 2004). Recent data show that in genetically zyxin-deficient fibroblasts, focal adhesions are depleted from Mena and VASP, and that cells lacking zyxin display deficits in actin cytoskeleton remodelling (Hoffman et al, 2006).…”

Zyxin emerges as a key player in the mechanotransduction at cell adhesive structures

“…Interestingly, cyclic stretching the substratum results in the translocation of zyxin from FAs to nuclei in smooth muscle cells. 46 This translocation of zyxin may be involved in the mechano-induced gene transcription, because zyxin family proteins have been suggested to mediate transcription process through their interaction with transcription factors. 25 In this review, we discuss the role of zyxin as a key element of mechanotransducing systems at cell adhesive structures: force-dependent recruitment of zyxin to FAs, SFs and AJs would facilitate actin polymerization at these structures.…”

Retrograde Fluxes of Focal Adhesion Proteins in Response to Cell Migration and Mechanical Signals

“…Several proteins, including zyxin and vasodilator-stimulated phosphoprotein (VASP), are known to localize to a variable extent at focal adhesions (Crawford et al, 1992;Rottner et al, 2001), or to shuttle between focal adhesions and the nucleus (Nix and Beckerle, 1997;Aplin and Juliano, 2001). Recent studies further indicated that mechanical stimulation can induce the change in distribution of zyxin from focal adhesions to either actin stress fibers in cultured fibroblasts (Yoshigi et al, 2005), or the nucleus of vascular smooth muscle cells (Cattaruzza et al, 2004). The latter may be related to the suspected ability of zyxin to regulate gene expression (Degenhardt and Silverstein, 2001).…”