Vascular smooth muscle cell migration mediated by thrombin and urokinase receptor.
To determine whether thrombin directly modifies mobility of vascular smooth muscle cells (SMC), in Transwell systems (modified Boyden chambers), we exposed SMC to alpha-thrombin. In concentrations as low as 1 NIH U/ml, thrombin induced migration as well as proliferation of SMC. Inhibition of protein synthesis by cycloheximide (2 micrograms/ml) obviated thrombin's chemotactic effect. Neither gamma-thrombin nor D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK)-inactivated alpha-thrombin (both used as controls) exerted a chemotactic effect. Concomitant hirudin or antithrombin III plus heparin inhibited chemotaxis by thrombin when added up to 2 h after addition of thrombin. alpha-Thrombin increased SMC synthesis of urokinase receptor (uPAR) and its cell surface expression as shown by metabolic labeling and immunoprecipitation as well as by flow cytometry. Thus alpha-thrombin, in concentrations thought to be present in vivo at sites of vascular injury, can stimulate not only proliferation but also migration of vascular SMC though a mechanism(s) possibly involving synthesis of uPAR, which is known to influence migration in diverse types of cells. Accordingly, both proliferation and migration dependent on thrombin may accelerate atherosclerosis, restenosis, or both after interventions such as angioplasty.
Noda-Heiny
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Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Sobel
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BE
D000818:Animals; D002417:Cattle; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014176:Protein Biosynthesis; D011956:Receptors, Cell Surface / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D013917:Thrombin / Q000494:pharmacology / Q000502:physiology*; D013997:Time Factors
D008934:Mitogens; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D013917:Thrombin