(Circulation. 2001;103:597.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Endothelial Cells Inhibit Flow-Induced Smooth Muscle Cell Migration
Role of Plasminogen Activator Inhibitor-1
From the Department of Surgery, University of Rochester Medical Center, Rochester, NY (E.M.R., J.P.C., P.A.C., J.V.S., S.S.O.), and Department of Biochemistry, Holland Laboratory, Rockville, Md (S.S., D.A.L.).
Background—The endothelium may play a pivotal role in hemodynamic force–induced vascular remodeling. We investigated the role of endothelial cell (EC) plasminogen activator inhibitor-1 (PAI-1) in modulating flow-induced smooth muscle cell (SMC) migration.
Methods and Results—Human SMCs cocultured with or without human ECs were exposed to static (0 mL/min) or flow (26 mL/min; shear stress 23 dyne/cm2) conditions for 24 hours in a perfused capillary culture system. SMC migration was then assessed with a Transwell migration assay. In the absence but not in the presence of ECs, pulsatile flow significantly increased the migration of SMCs (264±26%) compared with SMCs under static conditions, concomitant with a 3- and 4-fold increase in PAI-1 mRNA and protein, respectively, in cocultured ECs. In the presence of PAI-1-/- ECs, flow increased wild-type SMC migration (226±25%), an effect that was reversed by exogenous PAI-1. To determine whether the antimigratory activity of PAI-1 was dependent primarily on inhibition of PAs or its association with vitronectin, experiments were conducted with PAI-1R (a mutant PAI-1 that binds to vitronectin but does not inhibit PA) and PAI-1K (a mutant that inhibits PA but has reduced affinity for vitronectin). PAI-1R inhibited both basal and flow-induced migration, whereas PAI-1K inhibited flow-induced migration in the absence of any effect on baseline migration.
Conclusions—Flow-induced EC PAI-1 inhibits flow-induced SMC migration in vitro. EC PAI-1 expression may be one of the predominant mechanisms responsible for controlling the process of vascular remodeling.
Key Words: endothelium • stress • atherosclerosis • muscle, smooth • plasminogen activators
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