Review ArticleVersican Degradation and Vascular Disease
Section snippets
The Nature of Versican in the Blood Vessel
Differential RNA splicing gives rise to four isoforms of versican (V0, V1, V2, and V3), which vary by the presence or absence of two glycosaminoglycan (GAG) binding domains named αGAG and βGAG (Figure 1). All forms of versican share the remaining domains that include the amino-terminal globular domain (G1; which contains the hyaluronan-binding link modules) and the carboxy-terminal G3 domain (which contains two EGF-like repeats, a complement-regulatory protein-like repeat [CRP], and a C-type
Proteinases Capable of Cleaving Versican
Several proteinase families are capable of producing the fragments of versican observed in vivo in the arterial wall. For example, matrix metalloproteinase (MMP)-1 (Perides et al. 1995), -2 (Passi et al. 1999), -3 (Perides et al. 1995, Halpert et al. 1996), -7 (Halpert et al. 1996), and -9 (Passi et al. 1999) have been shown to degrade native, purified versican in vitro. Whereas MMP-8 cleaves aggrecan, the activity of this MMP against versican has not been studied. Plasmin has been shown to
Versican in Intimal Hyperplasia
As treatments for the clinical symptoms of atherosclerosis, all forms of reconstruction of small arteries, including angioplasty, atherectomy, endarterectomy, stent angioplasty, and synthetic and vein bypass grafting, fail frequently because of lumenal narrowing, resulting in reduction in blood flow and thrombosis (Kester and Waybill 2001). Lumenal narrowing (stenosis or restenosis) is the consequence of intimal hyperplasia and pathologic remodeling. Remodeling refers to a change in the lumenal
Versican Metabolism in Intimal Regression
Regression of the neointima has been reported in several systems. In the rat carotid artery model of balloon catheter-mediated injury, neointimal hyperplasia occurs over a period of approximately 4 weeks and is followed by neointimal regression over the next 4 weeks (Nuthakki et al. 2004). Although data are not available on the fate of versican during the regression process in this model, it is of interest to note that immunohistochemical analysis of versican (using 2B1 against the G3 globular
Possible Role of Versican Breakdown Products in Vascular Disease
Overexpression experiments suggest that versican V1 stimulates cell proliferation, whereas versican V2 inhibits proliferation (Sheng et al. 2005). The converse experiments using antisense or siRNA also indicate that endogenous versican V1 increases proliferation, including that of SMCs (Zhang et al. 1999, Huang et al. 2006) (unpublished data, Rahmani M, Wong B, Allahverdian S, Cheung C, Carthy J, Keire P, Wight T, McManus B). These data are consistent with evidence that formation of
Future Directions
We have reviewed work that suggests that cleavage of versican into discrete fragments may occur not only as normal physiologic turnover of the vascular extracellular matrix, but also be involved in vascular pathology (Figure 6). The 70-kDa G1 fragment of versican formed by ADAMTS activity at the Glu441–Ala442 bond of V1 has been documented (Sandy et al. 2001), whereas other potential ADAMTS cleavage sites, such as Tyr423–Ile424 of V1, have been proposed based on activity against peptide
Acknowledgments
NIH HL18645 (TNW), HL30946 (RDK), Dianne Lynn Family Foundation (AP).
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2020, Matrix BiologyCitation Excerpt :Alternatively, the disappearance of Vcan could be due to other enzymes. Several proteinases including plasmin [30], leukocyte elastase and matrix metalloproteinases (MMPs), including MMP-1 [32], 2 [33], 3 [32,34], 7 [34], and 9 [33] cleave Vcan, and they are secreted from inflammatory cells such as neutrophils and macrophages. Analysis of versicanases revealed similar expression patterns among ADAMTS-1, 4, and 9, suggesting that their expression is regulated in a similar manner.