DEPENDENCE OF AUGMENTATION OF ARTERIAL ENDOTHELIAL-CELL EXPRESSION OFPLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1 BY INSULIN ON SOLUBLE FACTORS RELEASED FROM VASCULAR SMOOTH-MUSCLE CELLS

Background Insulin-resistant states are characterized by accelerated a therosclerosis and are associated with increased plasma concentrations of insulin and plasminogen activator inhibitor type 1 (PAI-1). To det ermine whether arterial expression of PAI-1 in response to insulin con tributes to the increased PAI-1 observed, human and porcine arteries i n culture were exposed to insulin, and results were compared with resp onses of specific arterial cellular constituents maintained in culture and coculture. Methods and Results Human and porcine arterial segment s and cells obtained from arteries were maintained in culture. insulin increased accumulation of PAI-1 in conditioned medium from arterial s egments (ng PAI-1 [1 nmol/L insulin minus control]: human arteries 47/-17, porcine arteries 3.1+/-1.2, P<.05 for each) and from endothelial cells (ECs) cocultured with smooth muscle cells (SMCs, ng PAI-1 [1 nm ol/L insulin minus control]: human cells 43+/-8, porcine cells 0.5+/-0 .1, P<.05 for each). Insulin had no effect on EC expression of PAI-1 w hen not cocultured with SMCs. Increased accumulation of PAI-1 was seen when ECs, in coculture chambers without SMCs, were cultured with medi um previously conditioned by SMCs in the presence of insulin. The incr eased accumulation of PAI-1 in conditioned medium was secondary to bot h an increased transport of PAI-1 from the basal to the apical surface of ECs as well as an increased production of PAI-1 by ECs. Conclusion s insulin augments arterial expression of PAI-1 by stimulating release of a soluble factor(s) from SMCs. Accordingly, increased arterial ela boration of PAI-1 in response to insulin is likely to account, in part , for the elevated PAI-1 observed in the blood of subjects with insuli n-resistant states.