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MT1-MMP (macrophages)

1 Enzymes not expressed in basal conditions.

MMP = Matrix metalloproteinase; MT-MMP = membrane-type MMP; ECs = endothelial cells; PMNs = polymorphonuclear neutrophils; SMCs = smooth muscle cells.

1 Enzymes not expressed in basal conditions.

MMP = Matrix metalloproteinase; MT-MMP = membrane-type MMP; ECs = endothelial cells; PMNs = polymorphonuclear neutrophils; SMCs = smooth muscle cells.

by tissue or plasma proteinases - plasmin, thrombin, other MMPs or MT-MMPs - and reactive oxygen species. The activation of MMPs and their inhibition by TIMPs are the main regulatory mechanisms of MMP activities in the vascular wall [35, 36]. The very well controlled balance between active proteinases and inhibitors is perturbed during pathological processes, particularly when polymorphonuclear neutrophils or macrophages are present. However, through their capacity to synthesize enzyme inhibitors, SMCs have an extremely high capacity to respond to these increased enzyme levels.

Functions in the Vascular Wall

The biomechanical properties of vessels, particularly of the major arteries, are largely dependent on the absolute and relative quantities of fibrillar collagens (and elastin) [38]. Collagen fibers run longitudinally in the intima and adventitia, and run spirally between muscle layers in the media [39]. These fibers are often crimped or 'wavy' in order to both allow and resist distension of the vessel [40]; The larger diameter type I fibers are believed to confer high tensile strength while the thinner, type III fibers are associated with increased tissue flexibility [41]; Molecules of fibrillar collagen type V can either form fine type V filaments or can copolymerize with type I and III molecules in larger fibers. It is believed that inclusion of type V molecules may regulate assembly and structure of the vascular collagen fiber network [42].

Vascular collagens may also interact with SMCs resulting in changes of their phenotype and activity. In fact, type I collagen promotes change to the synthetic phenotypic while type IV collagen inhibits, or even reverses, this change [43, 44]. In addition, interactions with the surrounding collagen matrix may control collagen production in phenotypically modified SMCs by posttranslational mechanisms. For instance, SMCs grown inside type I collagen lattices, unlike cells grown on plastic, do not dramatically increase fibrillar collagen secretion in response to serum and growth factors [45]. Serum increases transcription and translation of collagen mRNA in lattice cells, but intracellular degradation of the newly translated collagen prevents it from being secreted [46].

Finally, the possibility exists that collagen and other ECM molecules participate in the regulation of vascular tone. Recently, Davis et al. [47] defined matricryptic sites as biologically active sites that are not exposed in the mature secreted form of ECM molecules, but which become exposed following con-formational or structural changes in these molecules (e.g., the Arg-Gly-Asp peptide or RGD sequence). The same authors hypothesized that exposure of matricryptic sites in altered ECM molecules is a critical component of a coordinated vascular response to tissue injury. In support of this notion, they showed that proteolytic fragments of collagen type I (which contain the RGD sequence) induce vasoconstriction [48, 49]. Furthermore, it has been shown that these molecules induce integr in-dependent vasoconstrictor effects that are regulated through calcium signaling and which are mediated in some cases by the L-type calcium channel of SMCs [48].

Vascular Elastin and Other ECM Molecules

Elastin is the most abundant protein of the large arteries that are subjected to a large pulsatile pressure generated by cardiac contraction [50-52]. However, elastin is also detectable in resistance arteries - mainly in the internal and external elastic lamina - and veins. Elastin represents 90% of the elastic fibers, the other constituents being microfibrillar glycoproteins such as fibrillins and microfibrillar-associated glycoproteins [53-55]. The precursor of elastin, tro-poelastin, is a highly hydrophobic protein which is soluble in salt solution like the collagen triple helix. In contrast, elastin is an insoluble protein. This insolubility results from the cross-linking process between lysine residues. Cross-linking of tropoelastin molecules begins with the oxidative deamination of some lysine residues by lysyl oxidase, as previously described for collagen cross-linking. The spontaneous condensation reaction between four lysine/al-lysine residues leads to the formation of the specific cross-links for elastin, desmosine and isodesmosine. Cross-links resulting from the condensation of two or three lysine/allysine residues are also detectable in elastin [33]. This cross-linking process confers to elastin its function, i.e. elasticity, essential in large arteries which distend during systole and recoil during diastole. Another property of elastin has been recently demonstrated by the study of patients suffering from supravalvular aortic stenosis and of knockout mice for elastin: elastin controls, directly or indirectly, the proliferation and phenotype of SMCs [56-58].

Other structural glycoproteins play an essential role in the structure and function of the ECM in the arterial wall, including fibronectin, vitronectin, laminin, entactin/nidogen, tenascin and thrombospondin. These glycopro-teins have a multidomain structure, potentially enabling simultaneous interactions between cells and other ECM components [59, 60].

The proteoglycans contained in the vascular wall are the large aggregating proteoglycans aggrecan and versican, the small non-aggregating interstitial proteoglycans biglycan, decorin and fibromodulin and the cell-associated proteoglycans syndecan, fibroglycan and glypican. Proteoglycans are proteins that have one or more attached glycosaminoglycan chains [61, 62]. They contain distinct protein and carbohydrate domain structures, which interact with other ECM molecules. They participate in ECM assembly and confer specific properties to the tissues (hydration, filtration, etc.). Proteoglycans also regulate various cellular activities (proliferation, differentiation, adhesion, migration) and control cytokine biodisponibility and stability (basic fibroblast growth factor, transforming growth factor-P or TGF-P, etc.) [63].

Vascular Integrins

Integrins are a large family of cell surface receptors that provide for adhesion of cells to both the ECM and neighboring cells. In addition, integrins act as a membrane coupling and assembly point for a growing list of cytoskeletal and cell signaling components. Of the approximately 24 known integrins, 16 have been reported to have involvement in some aspect of vascular biology (table 4), including the processes involved in the synthesis, degradation, and structural modification of the ECM [64].

As early as 1976, Leung et al. [65] had shown that SMCs grown on elastic sheets and stimulated by cyclic strain upregulate their synthesis of collagen I and III. Integrins are the best candidates for being the mechanosensors capable of detecting changes in stress and strain. In addition to their role in regulating ECM production, integrins also participate in controlling the production of several MMPs. Type VIII collagen binding of a1p1 and a2p integrins stimulates MMP-2 and MMP-9 expression and activity in SMCs [ 66]. while osteopontin and tenascin-C do so through ligation of the a^ integrin [67,68].

Table 4. Integrin heterodimers present in vascular cells

Endothelial

Smooth muscle

cells

cells

aft

aft

a2p1

a2p1

a3p1

a3p1

a5p1

a4p1

a6p1

a5p1

a6p4

a6p1

ay^3

a7p1

ay^5

a8p1

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