Endothelial Cells Inhibit Flow-Induced Smooth Muscle Cell Migration

Eileen M. Redmond, John P. Cullen, Paul A. Cahill, James V. Sitzmann, Steingrimur Stefansson, Daniel A. Lawrence, S. Steve Okada
2001 Circulation  
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/cm 2 ) conditions for 24 hours in a perfused capillary culture system. SMC migration was then
more » ... ion 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 (264Ϯ26%) 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-1Ϫ/Ϫ ECs, flow increased wild-type SMC migration (226Ϯ25%), 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. (Circulation. 2001;103: 597-603.)
doi:10.1161/01.cir.103.4.597 pmid:11157728 fatcat:ax43k24onvcl5oab34gevtci7y