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Although many mechanisms, including tran scriptional and translational controls and secretion and activation of proenzymes, are involved in the regulation of extracellular proteolysis, one mechanism that appears to be particularly relevant to cell migration and morpho genesis is spatial localization.Spatial localization, which appears to have evolved to concentrate proteoly sis near the cell surface as well as to restrict its activity to the immediate per icellu lar environment, can be achieved by two mechanisms: first, by binding to cellsurface receptors and matrixbinding sites, and second, by the coproduction of protease inhibitors.By preserv ing matrix integrity and thereby ensuring normal tissue architecture, protease inhibitors play an important per missive role during angiogenesis.These findings have led to the notion that a precise proteaseantiprotease equilibrium allows for localized pericellular matrix degradation during cell migration, while at the same time protecting the extracellular matrix against Eplerenone inappro priate destruction.However, since the net balance of proteolysis required for invasion is always likely to be positive, it has been suggested that antiproteolysis could be effective in inhibiting angiogenesis.In this respect, the requirement for MMP and PA activity during experimentally induced Cyclosporine angiogenesis in vivo has been clearly demonstrated.Accumulation of extravascular fibrin is one of the hallmarks of angiogenesis.Fibrin accumulates in the extracellular milieu after injury and also as a conse ing inflammation and in tumors.In contrast to matrices composed of collagen or other macromolecules, fibrin constitutes a provisional matrix that is progressively removed and replaced by other matrix components, including collagen.Although the mechanisms by which fibrin induces mature matrix formation are poorly under stood, fibrin itself is chemotactic for inflammatory cells and has been shown to regulate endothelial cell and fibroblast migration.In essence, mice deficient in plasminogen or doubly deficient in uPA and tPA have no obvious phenotypic abnormalities at birth.However, progressive multipleorgan failure occurs in young adult mice and appears to be the result of generalized microvascular thrombosis as well as widespread extravascular fibrin accumula tion.Definitive proof for this hypothesis has come from observations on the phenotype of mice deficient in both plasminogen and fibrinogen: removal of fibrinogen was found to alleviate the diverse spontaneous patholo gies associated with plasminogen deficiency and restore wound healing time to normal.However, it has also been suggested that the lack of phe notype in knockout mice may be an indication that in certain settings, uPA, tPA, PAI, and plasmin ple, during development, in which fibrin is not a major component of the extracellular matrix.Thus, irrespective of the context, a consistent pattern of changes in expression of a cohort of genes will occur in endothelial cells in response to VEGF and bFGF.This might inc ludepro teases andpro tea se inhibitors as well as alterations in synthesis of matrix components and integrins.This hypothesis would predict that although uPA and uPA receptor are expressed by endothelial cells during angiogenesis, deletion of these genes would have no consequence in settings in which fibrin is not a major component of the extracellular matrix, and this in turn might account for the lack of a developmental phenotype in the knockout mice.

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