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Transforming growth factor-beta 1 modulates basic fibroblast growth factor-induced proteolytic and angiogenic properties of endothelial cells in vitro

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Published in The Journal of Cell Biology. 1990, vol. 111, no. 2, p. 743-755
Abstract Tightly controlled proteolytic degradation of the extracellular matrix by invading microvascular endothelial cells is believed to be a necessary component of the angiogenic process. We have previously demonstrated the induction of plasminogen activators (PAs) in bovine microvascular endothelial (BME) cells by three agents that induce angiogenesis in vitro: basic FGF (bFGF), PMA, and sodium orthovanadate. Surprisingly, we find that these agents also induce plasminogen activator inhibitor-1 (PAI-1) activity and mRNA in BME cells. We also find that transforming growth factor-beta 1 (TGF-beta 1), which in vitro modulates a number of endothelial cell functions relevant to angiogenesis, also increases both PAI-1 and urokinase-type PA (u-PA) mRNA. Thus, production of both proteases and protease inhibitors is increased by angiogenic agents and TGF-beta 1. However, the kinetics and amplitude of PAI-1 and u-PA mRNA induction by these agents are strikingly different. We have used the ratio of u-PA:PAI-1 mRNA levels as an indicator of proteolytic balance. This ratio is tilted towards enhanced proteolysis in response to bFGF, towards antiproteolysis in response to TGF-beta 1, and is similar to that in untreated cultures when the two agents are added simultaneously. Using an in vitro angiogenesis assay in three-dimensional fibrin gels, we find that TGF-beta 1 inhibits the bFGF-induced formation of tube-like structures, resulting in the formation of solid endothelial cell cords within the superficial parts of the gel. These results suggest that a net positive proteolytic balance is required for capillary lumen formation. A novel perspective is provided on the relationship between extracellular matrix invasion, lumen formation, and net proteolytic balance, thereby reflecting the interplay between angiogenesis-modulating cytokines such as bFGF and TGF-beta 1.
Keywords Amino Acid SequenceAnimalsBase SequenceCattleCells, CulturedDNA/genetics/isolation & purificationEndothelium, Vascular/cytology/drug effects/ physiologyEnzyme InductionFibroblast Growth Factors/ pharmacologyKineticsMolecular Sequence DataNeovascularization, PathologicPeptide Hydrolases/ geneticsPlasminogen Activators/biosynthesis/ geneticsPlasminogen InactivatorsProtein Precursors/ geneticsRNA, Messenger/geneticsRestriction MappingTetradecanoylphorbol Acetate/pharmacologyTranscription, Genetic/ drug effectsTransforming Growth Factors/ pharmacologyUrokinase-Type Plasminogen Activator/biosynthesis/ geneticsVanadates/pharmacology
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PMID: 1696269
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Other version: http://jcb.rupress.org/content/111/2/743.full.pdf
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PEPPER, Michael Sean et al. Transforming growth factor-beta 1 modulates basic fibroblast growth factor-induced proteolytic and angiogenic properties of endothelial cells in vitro. In: The Journal of Cell Biology, 1990, vol. 111, n° 2, p. 743-755. https://archive-ouverte.unige.ch/unige:8959

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Deposited on : 2010-07-12

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