Plasminogen activator inhibitor-1 deficiency enhances flow-induced smooth muscle cell migration.
BACKGROUND
We determined the role of smooth muscle cell (SMC)-derived plasminogen activator inhibitor-1 (PAI-1) in the flow-induced SMC migratory response.


METHODS
Wild type (wt) or PAI-1 knockout SMC were cultured in the absence or presence of endothelial cells (EC) under static or pulsatile flow conditions in a perfused culture system. SMC migration was then assessed by Transwell assay.


RESULTS
Pulsatile flow significantly increased SMC PAI-1 mRNA and protein levels, approximately 4- and 3-fold respectively (n = 4, p < 0.05). In the absence, but not in the presence of EC, pulsatile flow significantly increased ( approximately 2.4-fold) the migration of wt SMC when compared to wt SMC cultured under static conditions. PAI-1 -/-SMC migration was significantly increased under flow conditions as compared to wild-type controls (334 +/- 22% vs. 237 +/- 11%, n = 6, p < 0.05). This flow-induced migration was significantly attenuated, but not completely inhibited, when PAI-1 -/-SMC were cultured in the presence of EC (147 +/- 13%, n = 6, p < 0.05). The flow-induced PAI-1 -/-SMC migratory response was partially inhibited by an anti-urokinase plasminogen activator (uPA) antibody (#1189), and completely inhibited by both 1189 and the matrix metalloproteinase (MMP) inhibitor BB3103. In parallel PAI-1 -/-SMC cells, there was a greater flow-induced increase in proMMP-2 activity as compared to wild-type control cells. Moreover, under both static and flow conditions, tissue inhibitors of matrix metalloproteinases (TIMP)-2 activity was reduced in these PAI-1-deficient cells as compared to wild-type controls.


CONCLUSIONS
These results suggest that SMC PAI-1 plays a role in limiting flow-induced SMC migration and thus may be an important mechanism for controlling the process of vascular remodelling.
Cullen
John P
JP
Department of Surgery, University of Rochester Medical Center, Box SURG, 601 Elmwood Avenue, Rochester, NY 14642-8410, USA.
Nicholl
Suzanne M
SM
Sayeed
Shariq
S
Sitzmann
James V
JV
Okada
S Steve
SS
Cahill
Paul A
PA
Redmond
Eileen M
EM
D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*
D017395:Plasminogen Activator Inhibitor 1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases