STATE OF THE ART ARTICLEDevelopment and Disease in Proteinase-Deficient Mice: Role of the Plasminogen, Matrix Metalloproteinase and Coagulation System
Section snippets
The Coagulation System
Initiation of the plasma coagulation system is triggered by tissue factor (TF), which functions as a cellular receptor and cofactor for activation of the serine proteinase factor VII (FVII) to factor VIIa (FVIIa) 1, 2, 3, 4. Activation of factor VII can be performed by FVIIa (autoactivation), factor IX, factor X, factor XII, thrombin, or hepsin [2]. The TF·FVIIa complex activates factor X either directly or indirectly via activation of factor IX, resulting in the activation of prothrombin to
The Plasminogen System
The plasminogen system is composed of an inactive proenzyme plasminogen (Plg) that can be converted to plasmin by either of two plasminogen activators (PA), tissue-type PA (t-PA) or urokinase-type PA (u-PA) 29, 30. This system is controlled at the level of plasminogen activators by plasminogen activator inhibitors (PAIs) of which PAI-1 is believed to be physiologically the most important 31, 32, 33, and at the level of plasmin by a2-antiplasmin [29]. Due to its fibrin-specificity, t-PA is
Matrix Metalloproteinases
Matrix metalloproteinases (MMPs) constitute a rapidly expanding family of proteinases able to degrade most extracellular matrix components 46, 47, 48, 49. In the mouse, MMP-13 (collagenase 3) is the primary interstitial collagenase, whereas MMP-2 (gelatinase-A) and MMP-9 (gelatinase-B) degrade collagen type IV, V, VII, and X, elastin and denatured collagens. The stromelysins-1 and -2 (MMP-3 and MMP-10) and matrilysin (MMP-7) break down the proteoglycan core proteins, laminin, fibronectin,
Embryonic Hemostasis
Following initial differentiation of stem cells into endothelial cells and their assembly into endothelial cell-lined channels (vasculogenesis), the embryonic vasculature further develops via sprouting of new channels from pre-existing vessels (angiogenesis), a process that is recapitulated in adulthood during tissue neovascularization 62, 63. Once the endothelial cells are assembled into vascular channels, they become surrounded by smooth muscle cells (large vessels) or pericytes (small
Neointima Formation
Vascular interventions for the treatment of atherothrombosis induce “restenosis” of the vessel within 3–6 months in 30–50% of treated patients 119, 120. The risk and costs associated with reinterventions represent a significant medical problem, mandating a better understanding at the molecular level of this process. Arterial stenosis may result from remodelling of the vessel wall (such as occurs predominantly after balloon angioplasty) and/or from accumulation of cells and extracellular matrix
Atherosclerosis
Atherosclerotic lesions initially consist of subendothelial accumulations of foamy macrophages (fatty streaks), which subsequently develop into fibroproliferative lesions by infiltration of myofibroblasts and accumulation of extracellular matrix [145]. A fibrous cap rich in smooth muscle cells and extracellular matrix overlies a central necrotic core containing dying cells, calcifications and cholesterol crystals. As long as these lesions do not critically limit blood flow, they may grow
Graft Arterial Disease
The obstruction of the lumen due to intimal thickening (resulting from accumulation of smooth muscle cells, leukocytes and extracellular matrix, and leading to tissue ischemia) significantly limits the success of organ transplantation in a majority of patients. A mouse model of transplant arteriosclerosis has been developed, that mimics in many ways the accelerated arteriosclerosis in coronary arteries of transplanted cardiac allografts in man 140, 163. In this model, host-derived leukocytes
Myocardial Ischemia
Acute myocardial infarction due to occlusion of coronary arteries is a leading cause of morbidity and mortality in Western societies. It depresses cardiac performance, and may induce arrhythmias, infarct expansion, ventricular wall rupture, and aneurysm formation 146, 147. Although proteinases have been implicated in cardiac remodeling 164, 165, 166, 167, 168, 169, 170 and in growth and remodeling of collateral vessels [171], today, surprisingly little is known about their in vivo relevance.
Angiogenesis
Migration of endothelial cells involves proteolysis of the extracellular matrix. Quiescent endothelial cells constituvely express t- PA, MMP-2, and minimal MMP-1 29, 30, 48. Net proteolysis is, however, prevented by coincident expression of PAI-1, TIMP-1, and TIMP-2 32, 128. In contrast, when endothelial cells migrate, they significantly upregulate u-PA, u-PAR, and, to a lesser extent, t-PA at the leading edge of migration 36, 48, 129, 132, 172. Although PAI-1 is also increased, its expression
Tumor Growth and Dissemination
Pericellular plasmin proteolysis has been proposed to play a role in tumor invasion and metastasis by facilitating the migration of malignant cells through anatomical barriers via degradation of extracellular matrix constituents. Increased expression of u-PA, u-PAR, and PAI-1 by tumor cells or by the surrounding stroma has indeed been observed 201, 202, 203, 204. In addition, use of antisense mRNA, or administration of natural or synthetic serine proteinase inhibitors, u-PAR antagonists, or of
Kidney
Plasminogen activators have been implicated in renal biology [30]. u-PA is released in the urine by the epithelial cells lining the straight proximal and distal tubules, whereas t-PA is produced by glomerular cells and by epithelial cells lining the distal part of the collecting ducts [230]. Impaired fibrinolysis, resulting from reduced u-PA or increased PAI-1 activity, has been implicated in the deposition of fibrin and of extracellular matrix components in chronic renal inflammatory disorders
Infection
The expression of proteinases (in particular of the u-PA:u-PAR system) is thought to be critical for the ability of leukocytes to degrade matrix proteins and to traverse tissue planes during recruitment to inflammatory sites. u-PA has, however, also been implicated in the modulation of cytokine and growth factor expression. It is required for TNF-α expression by mononuclear phagocytes, for activation of latent TGFβ-1 [42], and may also be involved in the release of interleukin-1 (IL-1) [249].
Conclusions
Gene targeting studies are useful to obtain novel insights into the role and relevance of a gene during normal or pathological biological processes in vivo. New insights into the role of the plasminogen, matrix metalloproteinase and the coagulation system in the formation of a normal blood vessel and in its pathologic progression to disorders such as thrombosis, restenosis, and atherosclerosis have recently been obtained. Several coagulation factors appear to play an unanticipated role in the
Acknowledgements
The authors are grateful to the members of the Center for Transgene Technology and Gene Therapy and to all external collaborators who contributed to these studies.
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