Up-regulation of connexin43 correlates with increased synthetic activity and enhanced contractile differentiation in TGF-β-treated human aortic smooth muscle cells

Rama, Aisha; Matsushita, T.; Charolidi, Nicoletta; Rothery, Stephen; Dupont, Emmanuel; Severs, Nicholas J.

doi:10.1016/j.ejcb.2005.11.007

Cited by 41 publications

(27 citation statements)

References 42 publications

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“…31 Although traditionally it has been thought that smooth muscle cells existed in either a synthetic or contractile state, it is now being recognized that there is considerable heterogeneity in smooth muscle cell populations and in some instances, contractile differentiation markers may be expressed simultaneously with matrix synthesis. [33][34][35] Our data are in support of this idea that contractile differentiation and increased matrix synthesis are not mutually exclusive in vascular smooth muscle cells. In fact, these cells appear to resemble a myofibroblast-like cell type in nature, which is a specialized wound repair fibroblast characterized by increased contractile ability and matrix synthesis.…”

Section: Discussionsupporting

confidence: 79%

“…A recent report has demonstrated that TGF-b also induced a contractile and synthetic phenotype in vascular smooth muscle cells, which correlated with increased connexin 43 expression and intercellular communication. 35 When taken together, these studies imply a role for connexin 43 in the Wnt3a-and TGF-b-mediated smooth muscle cell differentiation and matrix synthesis. In support of this idea, recent studies have highlighted a potential role for connexin 43 hemichannels in regulating vascular smooth muscle cell phenotype in response to balloon injury and other mitogenic stimuli.…”

Section: Discussionmentioning

confidence: 99%

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WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

Carthy

Luo

McManus

2012

Laboratory Investigation

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Evidence suggests a role for Wnt signaling in vascular wound repair and remodeling events. Despite this, very little is known about the effect of Wnt ligands on the structure and function of vascular cells. In this study, we treated vascular smooth muscle cells with 250 ng/ml of recombinant Wnt3a for 72 h and observed changes in the cell phenotype. Our data suggest Wnt3a completely alters the phenotype of vascular smooth muscle cells. The Wnt3a-treated cells appeared larger and had increased formation of stress fibers. These cells also had increased expression of the smooth muscle contractile proteins, calponin and smooth muscle a-actin, and contracted a collagen lattice faster than control cells. The Wnt3a-treated smooth muscle cells displayed increased extracellular matrix synthesis, as measured by collagen I and III mRNA expression, along with increased expression of MMP2 and MMP9, but decreased TIMP2 levels. The Wnt3a-induced change in cell phenotype was associated with increased expression of the gap junction protein connexin 43. Consistent with this, Wnt3a-treated smooth muscle cells displayed enhanced intercellular communication, as measured by the scrape-loading dye transfer technique. The canonical Wnt antagonist, dickkopf-related protein 1, completely reversed the contractile protein and connexin 43 expression seen in the Wnt3a-treated cells, suggesting these changes were dependent on canonical Wnt signaling. Collectively, this data suggest Wnt3a promotes a contractile and secretory phenotype in vascular smooth muscle cells that is associated with increased gap junction communication. Numerous studies have demonstrated that after arterial injury, vessel walls follow a response-to-injury pattern of wound healing leading to stenosis secondary to the neointimal accumulation of smooth muscle cells and extracellular matrix. 1-4 A number of soluble mediators released at the site of vascular injury act as molecular cues that guide smooth muscle cell responses during repair. 5,6 Growing evidence suggest a role for the Wnt family of secreted glycoproteins and their associated signaling pathways in regulating many of the processes involved in vascular wound repair and remodeling events. [7][8][9][10][11][12][13][14] However, the precise mechanisms and outcomes of Wnt signaling in such settings remain unclear. Moreover, the effect of specific Wnt family members on vascular cell phenotype remain undefined.The Wnt signaling pathway is best recognized for its role in the development of multi-cellular organisms, 15,16 and is critically involved in normal heart formation. 17 The Wnt family is comprised of 19 secreted glycoproteins that bind the Frizzled receptor and its co-receptor, lipoprotein receptorrelated proteins 5/6, to initiate an intracellular signaling cascade that controls the turnover of b-catenin. 18 In the absence of Wnt ligand, b-catenin is targeted for ubiquitinmediated degradation by the 26S proteasome. However, upon ligand stimulation, canonical Wnt signaling triggers a series of phosphorylation even...

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

Carthy

Luo

McManus

2012

Laboratory Investigation

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“…As described by the authors, the phosphorylation of Cx43 on serine 279/282, but not on serine 368, increased the vascular SMC proliferation. Moreover, treatment of human aortic SMCs with TGF-β upregulates Cx43 expression which is correlated with an increased synthetic activity [105]. Overall, these data suggest that atherosclerotic plaque development is influenced not only by the level of Cx43 expression but also by post-translational modifications.…”

Section: In Atherosclerosis-induced Vascular Remodellingmentioning

confidence: 75%

Multiple Roles of Connexins in Atherosclerosis- and Restenosis-Induced Vascular Remodelling

Morel¹

2014

J Vasc Res

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Endothelial dysfunction is the initial step in atherosclerotic plaque development in large- and medium-sized arteries. This progressive disease, which starts during childhood, is characterized by the accumulation of lipids, macrophages, neutrophils, T lymphocytes and smooth muscle cells in the intima of the vessels. Erosion and rupture of the atherosclerotic plaque may induce myocardial infarction and cerebrovascular accidents, which are responsible for a large percentage of sudden deaths. The most common treatment for atherosclerosis is angioplasty and stent implantation, but these surgical interventions favour a vascular reaction called restenosis and the associated de-endothelialization increases the risk of thrombosis. This review provides an overview of the role of connexins, a large family of transmembrane proteins, in vascular remodelling associated with atherosclerosis and restenosis. The connexins expressed in the vascular wall are Cx37, Cx40, Cx43 and Cx45; their expressions vary with vascular territory and species. Connexins form hemichannels or gap junction channels, allowing the exchange of ions and small metabolites between the cytosol and extracellular space or between neighbouring cells, respectively. Connexins have important roles in vascular physiology; they support radial and longitudinal cell-to-cell communication in the vascular wall, and significant changes in their expression patterns have been described during atherosclerosis and restenosis.

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“…Intercellular gap junction (GJ) has been shown to play a pivotal role in the transformation of vascular smooth muscle cells (VSMCs) from the differentiated contractile state to the activated synthetic state (Matsushita et al, 2007;Rama et al, 2006). GJ channels are composed of connexins, a multigene family of conserved proteins.…”

Section: Introductionmentioning

confidence: 99%

Effects of Losartan and Ramipril on the connexin expression in a rabbit balloon injury model

Li¹,

Li²,

Duan³

et al. 2011

Afr. J. Pharm. Pharmacol.

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Intercellular gap junction (GJ) plays a pivotal role in the proliferation and transformation of vascular smooth muscle cells (VSMCs). This study was designed to test the hypothesis that expressions of the component proteins of gap junctions, connexins40 and 43 (Cx40 and Cx43), are up-regulated in arteries subjected to balloon injury and that this up-regulation can be suppressed by statin therapy. Transmission electron microscopy (TEM) revealed that there were abundant GJ between neointimal SMCs but fewer and smaller GJ after losartan and ramipril treatment. Reverse transcription-polymerase chain reaction and Western blot analysis showed the messenger ribonucleic acid (mRNA) and protein expressions of Cx40 and Cx43 were elevated after injury, and these elevations were suppressed by losartan and ramipril. Immunostaining showed the Cx40 and Cx43 expressions were consistently enhanced in the neointimal area after injury, which was decreased by losartan and ramipril treatment. Balloon injury causes up-regulation of Cx40 and Cx43 in neointimal SMCs. angiotensin-converting enzyme inhibitors (ACEIs) and AT 1 antagonist losartan can reduce the proliferation of SMCs, suggesting the rennin-angiotensin system (RAS) system plays an important role in the remodeling of GJ in the VSMCs under pathological conditions.

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Up-regulation of connexin43 correlates with increased synthetic activity and enhanced contractile differentiation in TGF-β-treated human aortic smooth muscle cells

Cited by 41 publications

References 42 publications

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

Multiple Roles of Connexins in Atherosclerosis- and Restenosis-Induced Vascular Remodelling

Effects of Losartan and Ramipril on the connexin expression in a rabbit balloon injury model

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