Cyclic strain stimulates early growth response gene product 1-mediated expression of membrane type 1 matrix metalloproteinase in endothelium

Matrix metal loproteinases (MMPs) are hypothesized to be involved in the processes of endothelial cell (EC) migration and matrix remodeling during angiogenesis. Although hemodynamic forces (such as blood pressure, wall tension, and shear stress) are considered to be strong stimuli for angiogenesis, the role of hemodynamic forces on the regulation of MMPs including membrane type 1 matrix metal loproteinase (MT1-MMP) has not been fully elucidated. To study this, rat microvascular EC were exposed to 60 cycles/minute of 24% maximum strain for up to 24 hours. MT1-MMP mRNA and protein increased in a time-dependent manner through 24 hours of exposure to cyclic strain. Cyclic strain induced early growth response gene product (Egr-1) mRNA and protein within 1 hour. A specific nucleoprotein complex was formed when an oligonucleotide containing binding sites for Sp1 and Egr-1 was incubated with nuclear extracts from EC exposed to 1 hour of cyclic strain. Antibodies to Egr-1 completely supershifted this complex. Increased binding of Egr-1 by cyclic strain to the MT1-MMP promoter correlated with enhanced transcriptional activity. These results suggest that cyclic strain up-regulates the Egr-1-mediated expression of MT1-MMP in rat microvascular EC, emphasizing the importance of hemodynamic forces in the regulation of MT1-MMP in vivo.