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Characterization of recombinant plasminogen activator production by primate
endothelial cells transduced with retroviral vectors
DA Dichek, SW Lee and NH Nguyen
Molecular Hematology Branch, National Heart, Lung and Blood Institute,
Bethesda, MD.
Retroviral vector-mediated expression of plasminogen activators (PAs) from
endothelial cells (ECs) has been proposed as a potential therapeutic
approach for intravascular thrombosis. To define the potential for gene
transfer to increase fibrinolytic activity in a primate system, baboon ECs
were transduced with retroviral vectors expressing wild-type and
glycosylphosphatidylinositol-anchored urokinase, as well as wild-type and
serpin-resistant tissue PA (t-PA). Expression of either t-PA or urokinase
was increased by one log over baseline levels. There was no specific effect
of either t-PA or urokinase overexpression on endogenous t-PA, urokinase,
or PA inhibitor 1 (PAI-1) expression. Recombinant urokinase could be
anchored to the cell surface at a level eight-fold above that of
receptor-bound urokinase. The majority of secreted urokinase accumulated in
conditioned medium as a free proenzyme, whereas both wild-type and
serpin-resistant t-PA accumulated almost exclusively in complexes with
PAI-1. In most but not all of the assays, the urokinase vectors conferred
PA activity above that of the t-PA vectors. These data show that PA
synthesis and activity are specifically increased subsequent to retroviral
vector-mediated gene transfer in primate ECs. However, definition of an
optimal PA vector will require in vivo experimentation.
Volume 84,
Issue 2,
pp. 504-516,
07/15/1994
Copyright © 1994 by The American Society of Hematology
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