Abstract 1102: Differential Effect of Wall Tension on Matrix Metalloproteinase Promoter Activation in the Thoracic Aorta
Vascular remodeling relies upon extracellular matrix restructuring by the matrix metalloproteinases (MMPs). Induction of MMP-2, MMP-9, and the membrane type-1 MMP (MT1-MMP) by biological signaling molecules has been defined, but whether a mechanical stimulus such as elevated wall tension may generate MMP promoter activation remains unknown. Accordingly, this study examined whether MMP promoter activation would occur as a function of wall tension. The MMP-2, MMP-9, or MT1-MMP promoter sequences were fused to a reporter gene (lacZ or luciferase) and inserted into the mouse genome. Thoracic aortic rings were harvested (4 – 6 preparations/construct) and maintained under physiological conditions at predetermined tension values corresponding to 69, 83 and 99 mmHg for 3 hours. Relative gene expression of lacZ or luciferase, directly reflecting MMP promoter activity, was then quantified by RT-PCR. MMP-2 promoter activity increased at the greatest wall tension application, whereas MMP-9 was unaffected (Figure⇓). MT1-MMP activity was increased at both 83 and 99 mmHg. Using unique transgenic constructs with homology to human MMP promoters, this study demonstrated that a physiologically relevant mechanical stimulus was sufficient to differentially induce MMP promoter activation. MT1-MMP activates proMMP-2, and parallel induction of these specific MMPs would cause heightened proteolytic activity. Moreover, these data suggest that selective MMP induction occurs at wall tension values concordant with hypertension and that a mechanical-molecular set point exists which triggers adverse remodeling within the vascular wall.