Cyclic strain increases protease-activated receptor-1 expression in vascular smooth muscle cells

Cyclic strain regulates many vascular smooth muscle cell (VSMC) functions t hrough changing gene expression. This study investigated the effects of cyc lic strain on protease-activated receptor-1 (PAR-1) expression in VSMCs and the possible signaling pathways involved, on the basis of the hypothesis t hat cyclic strain would enhance PAR-1 expression, reflecting increased thro mbin activity. Uniaxial cyclic strain (1 Hz, 20%) of cells cultured on elas tic membranes induced a 2-fold increase in both PAR-1 mRNA and protein leve ls. Functional activity of PAR-1, as assessed by cell proliferation in resp onse to thrombin, was also increased by cyclic strain. In addition, treatme nt of cells with antioxidants or an NADPH oxidase inhibitor blocked strain- induced PAR-1 expression. Preincubation of cells with protein kinase inhibi tors (staurosporine or Ro 31-8220) enhanced strain-increased PAR-1 expressi on, whereas inhibitors of NO synthase, tyrosine kinase, and mitogen-activat ed protein kinases had no effect. Cyclic strain in the presence of basic fi broblast growth factor induced PAR-1 mRNA levels beyond the effect of cycli c strain alone, whereas no additive effect was observed between cyclic stra in and platelet-derived growth factor-AB. Our findings that cyclic strain u pregulates PAR-1 mRNA expression but that shear stress downregulates this g ene in VSMCs provide an opportunity to elucidate signaling differences by w hich VSMCs respond to different mechanical forces.