© 1998 American Heart Association, Inc.
Original Contributions |
Differential Regulation of Protease Activated Receptor-1 and Tissue Plasminogen Activator Expression by Shear Stress in Vascular Smooth Muscle Cells
From the Division of Cardiology, University of Texas Medical Branch (J.R., F.L., C.P., M.S.R.), Galveston; Institute of Biosciences and Bioengineering, Rice University (M.P., K.T.N., L.V.M.); and the Department of Cell Biology, Texas Biotechnology Corporation (S.G.E.), Houston, Tex.
Correspondence to Marschall S. Runge, MD, PhD, University of Texas Medical Branch, Division of Cardiology, 5.106 John Sealy Hospital, 301 University Blvd, Galveston, TX 77555-0553.
Abstract—Recent studies have demonstrated that vascular smooth muscle cells are responsive to changes in their local hemodynamic environment. The effects of shear stress on the expression of human protease activated receptor-1 (PAR-1) and tissue plasminogen activator (tPA) mRNA and protein were investigated in human aortic smooth muscle cells (HASMCs). Under conditions of low shear stress (5 dyn/cm2), PAR-1 mRNA expression was increased transiently at 2 hours compared with stationary control values, whereas at high shear stress (25 dyn/cm2), mRNA expression was decreased (to 29% of stationary control; P<0.05) at all examined time points (2 to 24 hours). mRNA half-life studies showed that this response was not due to increased mRNA instability. tPA mRNA expression was decreased (to 10% of stationary control; P<0.05) by low shear stress after 12 hours of exposure and was increased (to 250% of stationary control; P<0.05) after 24 hours at high shear stress. The same trends in PAR-1 mRNA levels were observed in rat smooth muscle cells, indicating that the effects of shear stress on human PAR-1 were not species-specific. Flow cytometry and ELISA techniques using rat smooth muscle cells and HASMCs, respectively, provided evidence that shear stress exerted similar effects on cell surface–associated PAR-1 and tPA protein released into the conditioned media. The decrease in PAR-1 mRNA and protein had functional consequences for HASMCs, such as inhibition of [Ca2+] mobilization in response to thrombin stimulation. These data indicate that human PAR-1 and tPA gene expression are regulated differentially by shear stress, in a pattern consistent with their putative roles in several arterial vascular pathologies.
Key Words: shear stress • protease activated receptor-1 • tissue plasminogen activator • smooth muscle cell
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