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Modulation of bovine microvascular endothelial cell proteolytic properties by inhibitors of angiogenesis

Wilks, J. W.
Schweigerer, L.
Published in Journal of cellular biochemistry. 1994, vol. 55, no. 4, p. 419-434
Abstract A tightly controlled increase in extracellular proteolysis, restricted both in time and space, is an important component of the angiogenic process, while anti-proteolysis is effective in inhibiting angiogenesis. By focussing on the plasminogen activator (PA)-plasmin system, the objective of the present studies was to assess whether previously described inhibitors of angiogenesis modify bovine microvascular endothelial cell proteolytic properties. We demonstrate that although synthetic angiostatic steroids (U-24067 and U-42129), heparin, suramin, interferon alpha-2a, and retinoic acid are all inhibitors of in vitro angiogenesis, each of these agents has distinct effects on the plasminogen-dependent proteolytic system. Specifically, angiostatic steroids and interferon alpha-2a reduce urokinase-type PA (u-PA) and PA inhibitor-1 activity, while heparin and retinoic acid increase u-PA activity. Suramin reduces cell-associated u-PA activity and greatly increases PAI-1 production at doses which induce monolayer disruption. These findings demonstrate that a spectrum of alterations in extracellular proteolysis is associated with anti-angiogenesis, and that anti-angiogenesis and anti-proteolysis are not necessarily correlated. A reduction in extracellular proteolysis would be expected to reduce invasion, whereas an increase in proteolysis might modulate the activity of inhibitory cytokines, which in turn could reduce endothelial cell proliferation and migration and inhibit angiogenesis. The spectrum of effects on different elements of the PA system observed in response to the agents assessed suggests that the role of modulations in extracellular proteolytic activity in anti-angiogenesis is likely to be varied and complex.
Keywords Adrenal Cortex/blood supplyAnimalsBetamethasone/analogs & derivatives/pharmacologyCattleCell Division/drug effectsCells, CulturedEndopeptidases/ metabolismEndothelium, Vascular/cytology/ drug effects/metabolismFibroblast Growth Factor 2/pharmacologyGene Expression/ drug effectsHeparin/pharmacologyHumansInterferon Alfa-2a/pharmacologyMicrocirculationNeovascularization, Pathologic/ prevention & controlPlasminogen Activator Inhibitor 1/biosynthesisProtease Inhibitors/ pharmacologyRecombinant Proteins/pharmacologySuramin/pharmacologyTranscription, Genetic/drug effectsTretinoin/pharmacologyUrokinase-Type Plasminogen Activator/biosynthesis
PMID: 7525617
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PEPPER, Michael Sean et al. Modulation of bovine microvascular endothelial cell proteolytic properties by inhibitors of angiogenesis. In: Journal of cellular biochemistry, 1994, vol. 55, n° 4, p. 419-434. doi: 10.1002/jcb.240550403 https://archive-ouverte.unige.ch/unige:9246

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