Extracellular Matrix Changes in Stented Human Coronary Arteries

Farb, Andrew; Kolodgie, Frank D.; Hwang, Jin‐Yong; Burke, Allen; Tefera, Kirubel; Weber, Deena K.; Wight, Thomas N.; Virmani, Renu

doi:10.1161/01.cir.0000139337.56084.30

Cited by 192 publications

(138 citation statements)

References 48 publications

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“…31 However, numerous vascular diseases are characterized by the accumulation of smooth muscle cells in the intimal layer of blood vessels where they are surrounded by newly synthesized extracellular Wnt3a alters smooth muscle cell phenotype JM Carthy et al matrix. 3,4,32 These cells are generally thought of as dedifferentiated and synthetic, in that they display a loss of contractile differentiation, but an increased capacity to synthesize matrix proteins. 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.…”

Section: Discussionmentioning

confidence: 99%

“…28 It has previously been reported that connexin 43 expression is upregulated in smooth muscle cells in response to injury in rodent models and in early human atherosclerosis, situations in which elevated Wnt signaling has been reported 7,14 and in which increased extracellular matrix synthesis is well documented. 3,38 Reducing connexin 43 expression has been shown to inhibit lesion development in rodent models of atherosclerosis and acute vascular injury, [39][40][41] suggesting potential pro-atherogenic functions for gap junction communication. Our data suggest Wnt3a increases the expression of connexin 43 in vascular smooth muscle cells, and this increase in connexin 43 expression is associated with increased intercellular communication and matrix synthesis.…”

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: Discussionmentioning

confidence: 99%

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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“…Furthermore, it would enable the physician to treat the population of patients (up to 30%) who actually develop a problem with stenosis or restenosis. Of particular interest from the perspective of this review, a consistent feature of acute intimal hyperplasia is the increased content of versican (Nikkari et al 1994, Finn et al 2002, Kenagy et al 2005, Chung et al 2002, Farb et al 2004. Therefore, understanding the mechanisms of intimal regression and the role of versican in this process is of great interest.…”

Section: Versican In Intimal Hyperplasiamentioning

confidence: 97%

“…Intimal atrophy occurs spontaneously in stented arteries after 6 months in humans (Asakura et al 1998) and 2 months in rats (Finn et al 2002, Langeveld et al 2004. At these late times during regression, the extracellular matrix (ECM) shows a relative loss of versican and a gain of collagen compared to earlier times (Chung et al 2002, Finn et al 2002, Langeveld et al 2004, Farb et al 2004. These data suggest that versican accumulates during neointimal progression and is lost during neointimal regression in the native artery.…”

Section: Versican Metabolism In Intimal Regressionmentioning

confidence: 99%

“…Recent reviews have focused on the role of versican generally and, more specifically, in vascular disease (Wight 2002, Wight andMerrilees 2004). For example, synthesis and deposition of versican in the extracellular matrix are acutely increased in the neointima after arterial injury caused by angioplasty, stents, or grafting (Nikkari et al 1994, Finn et al 2002, Kenagy et al 2005, Chung et al 2002, Farb et al 2004, Wight et al 1997, Matsuura et al 1996. In addition, there is selective accumulation of versican at the plaque thrombus interface in eroded human atherosclerotic plaques, suggesting a role for this proteoglycan in thrombosis ).…”

mentioning

confidence: 99%

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Versican Degradation and Vascular Disease

Kenagy

Plaas

Wight³

2006

Trends in Cardiovascular Medicine

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Versican is an abundant proteoglycan in the blood vessel wall that is increased after vascular injury and accumulates in advanced atherosclerotic plaques. Versican is a large molecule with domains that mediate binding to cytokines, enzymes, lipoproteins, other extracellular matrix molecules, and signaling receptors. There is evidence that versican exists in the normal, as well as the diseased, vessel wall as discrete fragments, which represent these functional domains. We review the literature on versican degradation in vascular tissue and the function of versican domains, all of which suggest that proteolytic modification of versican may have physiologic as well as pathologic implications for the vascular system.

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