APPOSITION-DEPENDENT INDUCTION OF PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1 EXPRESSION - A MECHANISM FOR BALANCING PERICELLULAR PROTEOLYSIS DURING ANGIOGENESIS

Plasminogen-activator inhibitor type I (PAI-1), the primary inhibitor of urinary-type plasminogen activator, is thought to play an important role in the control of stroma invasion by both endothelial and tumor cells. Using an in vitro angiogenesis model of capillary extension thr ough a preformed monolayer, in conjunction with in situ hybridization analysis, we showed that PAI-1 mRNA is specifically induced in cells j uxtaposed next to elongating sprouts. To further establish that PAI-1 expression is induced as a consequence of a direct contact with endoth elial cells, coculture experiments were performed. PAI-1 mRNA was indu ced exclusively in fibroblasts (L-cells) contacting endothelial cell ( LE-II) colonies, Reporter gene constructs driven by a PAI-1 promoter a nd stably transfected into L-cells were used to establish that both mo use and rat PAI-1 promoters mediate apposition-dependent regulation. T his mode of PAI-1 regulation is not mediated by plasmin, as an identic al spatial pattern of expression was detected in cocultures treated wi th plasmin inhibitors. Because endothelial cells may establish direct contacts with fibroblasts only during angiogenesis, we propose that fo cal induction of PAI-1 at the site of heterotypic cell contacts provid es a mechanism to negate excessive pericellular proteolysis associated with endothelial cell invasion. (C) 1998 by The American Society of H ematology.