Endothelial cells inhibit flow-induced smooth muscle cell migration - Roleof plasminogen activator inhibitor-1

Background-The endothelium may play a pivotal role in hemodynamic force-ind uced vascular remodeling. We investigated the role of endothelial cell (EC) plasminogen activator inhibitor-1 (PAI-1) in modulating flow-induced smoot h muscle cell (SMC) migration. Methods and Results-Human SMCs cocultured with or without human ECs were ex posed 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 migrati on was then assessed with a Transwell migration assay. In the absence but n ot in the presence of ECs, pulsatile flow significantly increased the migra tion of SMCs (264+/-26%) compared with SMCs under static conditions, concom itant 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-t ype 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, experim ents were conducted with PAI-1R (a mutant PAI-1 that binds to vitronectin b ut does not inhibit PA) and PAI-1K (a mutant that inhibits PA but has reduc ed affinity for vitronectin), PAI-1R inhibited both basal and flow-induced migration, whereas PAI-1K inhibited flow-induced migration in the absence o f any effect on baseline migration. Conclusions-Flow-induced EC PAI-1 inhibits flow-induced SMC migration in vi tro. EC PAI-1 expression may be one of the predominant mechanisms responsib le for controlling the process of vascular remodeling.