Mmp1

Small telopeptide

Interstitium

Lymph

Blood

Big telopeptide

(Interstitium) MMP-2, MMP-9

Degradation products

(Interstitium)

Fig. 2. Diagrammatic representation of fibrillar collagen turnover in the vascular wall. SMC = Smooth muscle cell; MMP = matrix metalloproteinase.

Synthesis and Secretion

While most of the collagens in the vascular intima and media are synthesized by smooth muscle cells (SMCs), fibroblasts are responsible for collagen synthesis in the adventitia. Contractile SMCs in the arterial media are responsible for the gross muscular changes that occur in the vessel in response to nervous and paracrine stimuli. These are quiescent cells which in the adult show little division, migration, or matrix production. SMCs are, however, phe-notypically plastic and can modulate to the so-called synthetic phenotype. These cells resemble the more immature fetal or neonatal cells and are commonly found in secondary culture and in the arterial intima; they migrate, divide, and produce ECM, namely collagen. Thus, a number of chemical and physical factors influence collagen production by SMCs through their pheno-typic modulation (table 2) [32].

After secretion of procollagen molecules in the extracellular compartment, the amino- and carboxy-terminal non-collagenous domains are removed by specific proteinases. The resulting collagen triple helices aggregate in quarter-staggered fibrils. Newly formed collagen fibrils are soluble in salt solutions and

Table 2. Factors influencing collagen synthesis and secretion by vascular smooth muscle cells

Stimulating factors

Transforming growth factor-ß

Platelet-derived growth factor

Angiotensin II

Periodic stretching

Insulin?

Aldosterone?

Inhibiting factors

Basic fibroblast growth factor Interferon-^ Tumor necrosis factor-a Prostaglandin E2 Cell-matrix contact Nitric oxide?

dilute acid, and have no tensile strength. During the formation of intermolecular cross-linking, collagen fibers become increasingly insoluble, more refractory to the action of enzymes and show a progressive increase in tensile strength. The cross-linking process is initiated by the enzyme lysyl oxidase, through the oxidation of specific lysine or hydroxylysine residues in the telopeptide regions. The resulting aldehydes undergo a series of reactions with adjacent reactive residues to give both inter- and intramolecular cross-links [33].

Degradation and Turnover

The metabolic turnover of mature collagen in adult animals is relatively slow [34]. Although only small amounts of these proteins are degraded normally, increased degradation and fragmentation of collagen fibers are observed in vascular diseases. Collagenolytic enzymes are found in a number of mammalian cells and tissues including polymorphonuclear neutrophils and mono-cytes/macrophages. Collagenolytic enzymes are mainly matrix metallopro-teinases (MMPs) and have been described extensively in previous reviews [35, 36]. Vascular MMPs include collagenases (MMP-1 and MMP-8), gelatinases (MMP-2 and MMP-9), elastases (MMP-7 and MMP-12), stromelysins (MMP-3) and membrane-type metalloproteinases (MT1-MMP) (table 3) . The substrate specificity differs for the various MMPs present in the vascular wall. Whereas MMP-1 degrades collagen types I and III, gelatinases act on gelatin and collagen type IV, and MMP-3 degrades proteoglycans, fibronectin, and laminin [37].

The proteolytic activity of each MMP is tightly regulated at three levels: first, gene expression and protein secretion levels; second, activation of the inactive pro-enzyme, and, third, inhibition by the tissue inhibitors of MMPs (TIMPs) or other inhibitors (a2-macroglobulin). The activation of secreted pro-MMPs requires the disruption of the Cys-Zn2+ (cysteine switch) interaction and the removal of the propeptide. In vivo, pro-MMPs are activated

Table 3. Metalloproteinases active on extracellular macromolecules present within the vascular wall and cellular origin

Detectable in vascular cells

Detectable in inflammatory cells

MMP-1 (ECs)1

MMP-1 (monocytes)

MMP-2 (ECs, SMCs, fibroblasts)

MMP-2 (macrophages, PMNs)

MMP-3 (SMCs) 1

MMP-7 (monocytes)

MMP-7 (SMCs)

MMP-8 (PMNs)

MMP-9 (ECs, SMCs, fibroblasts) 1

MMP-9 (macrophages, PMNs)

MT1-MMP (SMCs)

MMP-12 (macrophages)

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