Review Article
Versican Degradation and Vascular Disease

https://doi.org/10.1016/j.tcm.2006.03.011Get rights and content

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.

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).

References (55)

  • VK Nuthakki et al.

    Lysyl oxidase expression in a rat model of arterial balloon injury

    J Vasc Surg

    (2004)
  • AI Olin et al.

    The proteoglycans aggrecan and versican form networks with fibulin-2 through their lectin domain binding

    J Biol Chem

    (2001)
  • A Passi et al.

    The sensitivity of versican from rabbit lung to gelatinase A (MMP-2) and B (MMP-9) and its involvement in the development of hydraulic lung edema

    FEBS Lett

    (1999)
  • JD Sandy et al.

    Versican V1 proteolysis in human aorta in vivo occurs at the Glu445-Ala446 bond a site which is cleaved by recombinant ADAMTS-1 and ADAMTS-4

    J Biol Chem

    (2001)
  • RP Somerville et al.

    Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1

    J Biol Chem

    (2003)
  • TN Wight

    Versican: a versatile extracellular matrix proteoglycan in cell biology

    Curr Opin Cell Biol

    (2002)
  • Y Wu et al.

    Identification of the motif in versican G3 domain that plays a dominant-negative effect on astrocytoma cell proliferation through inhibiting versican secretion and binding

    J Biol Chem

    (2001)
  • Y Wu et al.

    beta 1-Integrin-mediated glioma cell adhesion and free radical-induced apoptosis are regulated by binding to a C-terminal domain of PG-M/versican

    J Biol Chem

    (2002)
  • Y Zhang et al.

    The G3 domain of versican enhances cell proliferation via epidermal growth factor-like motifs

    J Biol Chem

    (1998)
  • M Asakura et al.

    Remodeling of in-stent neointima, which became thinner and transparent over 3 years—serial angiographic and angioscopic follow-up

    Circulation

    (1998)
  • NA Cross et al.

    The expression and regulation of ADAMTS-1, -4, -5, -9, and -15, and TIMP-3 by TGFbeta1 in prostate cells: relevance to the accumulation of versican

    Prostate

    (2005)
  • E Di Cera

    Atherosclerosis: testing the water

    Arterioscler Thromb Vasc Biol

    (2003)
  • SP Evanko et al.

    Formation of hyaluronan- and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells

    Arterioscler Thromb Vasc Biol

    (1999)
  • A Farb et al.

    Extracellular matrix changes in stented human coronary arteries

    Circulation

    (2004)
  • AV Finn et al.

    A novel rat model of carotid artery stenting for the understanding of restenosis in metabolic diseases

    J Vasc Res

    (2002)
  • M Formato et al.

    Evidence for a proinflammatory and proteolytic environment in plaques from endarterectomy segments of human carotid arteries

    Arterioscler Thromb Vasc Biol

    (2003)
  • RL Geary et al.

    Wound healing: a paradigm for lumen narrowing after arterial reconstruction

    J Vasc Surg

    (1998)
  • Cited by (80)

    • Biology of Proteoglycans and Associated Glycosaminoglycans

      2021, Comprehensive Glycoscience: Second Edition
    • Extracellular Matrix in Vascular Disease, Part 2/4: JACC Focus Seminar

      2020, Journal of the American College of Cardiology
    • Accumulation of versican facilitates wound healing: Implication of its initial ADAMTS-cleavage site

      2020, Matrix Biology
      Citation 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.

    View all citing articles on Scopus
    View full text