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Dependence of augmentation of arterial endothelial cell expression of plasminogen activator inhibitor type 1 by insulin on soluble factors released from vascular smooth muscle cells.

BACKGROUND
Insulin-resistant states are characterized by accelerated atherosclerosis and are associated with increased plasma concentrations of insulin and plasminogen activator inhibitor type 1 (PAI-1). To determine whether arterial expression of PAI-1 in response to insulin contributes to the increased PAI-1 observed, human and porcine arteries in culture were exposed to insulin, and results were compared with responses of specific arterial cellular constituents maintained in culture and coculture.


METHODS AND RESULTS
Human and porcine arterial segments and cells obtained from arteries were maintained in culture. Insulin increased accumulation of PAI-1 in conditioned medium from arterial segments (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 nmol/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 when not cocultured with SMCs. Increased accumulation of PAI-1 was seen when ECs, in coculture chambers without SMCs, were cultured with medium previously conditioned by SMCs in the presence of insulin. The increased accumulation of PAI-1 in conditioned medium was secondary to both 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.


CONCLUSIONS
Insulin augments arterial expression of PAI-1 by stimulating release of a soluble factor(s) from SMCs. Accordingly, increased arterial elaboration 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 insulin-resistant states.