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Cardiovascular Research 2002 53(4):779-781; doi:10.1016/S0008-6363(02)00235-3
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Vitronectin is implicated as the matrix takes control of neointima formation

Andrew C. Newby*

Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Level 7, Bristol BS2 8HW, UK

* Tel.: +44-117-928-3582; fax: +44-117-928-3581 a.newby{at}bris.ac.uk

Received 28 December 2001; accepted 28 December 2001

KEYWORDS Extracellular matrix; Artherosclerosis

See article by Dufourcq et al. [9] (pages 953–963) in this issue.

The normal blood vessel wall contains two functionally distinct types of vascular extracellular matrix, namely basement membranes and interstitial matrix. A basement membrane consisting of type IV collagen, the multi-adhesive glycoprotein, laminin, and a variety of heparan sulphate proteoglycans, surrounds all quiescent, contractile smooth muscle cells (SMCs). Basement membranes maintain the contractile phenotype, since plating freshly isolated SMCs onto type IV collagen or laminin retards transition to the activated, synthetic phenotype characteristic of vascular repair [1]. Cell surface integrins most likely transduce the effects of type IV collagen and laminin; {alpha}1β1 and {alpha}7β1 integrins are implicated, respectively, and both are present in quiescent SMC [2]. In addition, basement-membrane proteoglycans directly inhibit SMC proliferation [3], sequester potent heparin binding growth factors (e.g. fibroblast growth factors [4,5]) and activate latent transforming growth factor-β (TGF-β), which inhibits SMC proliferation [6].

The interstitial matrix contains mainly strength-giving fibrillar types-I and -III collagens with smaller quantities of other fibril-associated collagens. Chondroitin sulphate and dermatan sulphate proteoglycans provide turgor as well as regulatory interactions [7]. In the larger arteries there is also a honeycomb of elastin, which may inhibit SMC proliferation by binding to a non-integrin elastin laminin receptor [8]. A variety of multiadhesive glycoproteins, including fibronectin, together with smaller amounts of osteopontin, thrombospondin and tenascin are present in normal vessels. The work by Dufourcq and colleagues in this volume [9] expands their previous finding [10] that SMC can synthesise another multiadhesive glycoprotein, vitronectin. Only low levels of vitronectin are present by immunocytochemistry in the interstitial matrix of uninjured blood vessels. Synthesis of vitronectin is also sluggish by in situ hybridisation in contractile SMCs [9], as is synthesis of other interstitial matrix components [11]. Moreover, receptors for vitronectin ({alpha}vβ3 and {alpha}vβ5 integrins) are downregulated in quiescent SMC [9], as are receptors for fibronectin ({alpha}vβ3 and {alpha}5β1 integrins) [2]. These data reinforce the concept that most cell matrix contacts of quiescent SMC are with the basement membrane components.

Vessel wall remodelling occurs as an adaptation to pressure and flow (e.g. in vein grafts) or mechanical (e.g. angioplasty) or biochemical (e.g. atherosclerosis) injury. These stimuli provoke SMC phenotypic modulation, migration and proliferation, which are orchestrated by changes in the extracellular matrix [12]. In particular, the basement membrane is degraded [13]. Indeed, secretion of matrix degrading enzymes, including plasminogen activators and matrix degrading metalloproteinases (MMPs) is dramatically increased and accelerates turnover of all matrix components [14]. The level of matrix protein synthesis increases [11,15] and the spectrum of expressed genes changes. Connective tissue growth factors, including platelet derived growth factor and TGF-β, are upregulated. Partly as a consequence, matrix components, including hyaluronan, fibrillar collagens (which are now prevalent in their monomeric forms), versican and fibronectin are increased [13–16]. Type VIII collagen [17] and the multi-adhesive glycoproteins, tenascin [18], thrombospondin [19,20] and osteopontin [21], are also upregulated. At the same time integrin receptors for fibronectin ({alpha}5β1) and for other glycoproteins ({alpha}vβ3) appear on the SMC surface [2]. Phenotypic modulation of SMC is promoted by fibronectin [1,22] and monomeric collagen [23]. The present work of Dufourcq and colleagues [9] extends this concept to include vitronectin by showing that expression of both vitronectin itself and its receptors, {alpha}vβ3 and {alpha}vβ5 integrins, is upregulated after balloon injury to the rat carotid artery. Moreover, continuous infusion of neutralising antibodies to vitronectin, {alpha}vβ3 or {alpha}vβ5 integrins into the adventitia of injured carotid arteries significantly reduces neointimal size and SMC numbers [9] but not the amount of neointimal matrix per cell. These changes are accompanied by a small decrease in SMC proliferation with anti-vitronectin only, and no change in levels of apoptosis. The main effect of the inhibitory antibodies is likely therefore to have been on SMC migration, for which direct evidence is provided from in vitro experiments on injured human SMC monolayers. The study of Duforcq et al. [9] provides a further rationale for previously published studies which implicated {alpha}vβ3 integrins in neointima formation [24,25]. Moreover, it provides a convincing case for adding vitronectin to the list of interstitial matrix glycoproteins that mediate activation of SMCs.

Although matrix remodelling after vascular injury was initially thought to be needed simply to detach cells from physical contacts with the matrix, a plethora of regulatory interactions are now recognised. For example, remodelling of collagen I may also reveal binding sites necessary for SMC migration [26]. In addition, binding to {alpha}5β1 appears to be critical for fibronectin polymerisation, cytoskeletal rearrangement and the promotion of SMC migration [27]. Engagement of {alpha}vβ3 facilitates migration on other glycoproteins, such as thrombospondin, osteopontin [25] and, as now shown, vitronectin [9]. Integrin engagement appears necessary to allow activation of calcium calmodulin activated kinase-II [28], a key signalling event in SMC migration. Similar mechanisms may underlie regulation of smooth muscle cell proliferation [12]. Engagement of integrins activates focal adhesion kinase and this facilitates growth factor-induced proliferation [29]. Binding to {alpha}vβ3 also allows downregulation of cyclin-dependent kinase inhibitors [30], thereby removing a brake on SMC proliferation. Downregulation of these inhibitors is a necessary step in the proliferative response of SMC cultured on monomeric collagen [31] and a key process underlying the suppression of SMC proliferation in intact rat aorta [32].


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