Pressure-induced matrix metalloproteinase-9 contributes to early hypertensive remodeling

Background - High blood pressure causes a change in vascular wall structure involving altered extracellular matrix composition, but how this process occurs is not fully understood. Methods and Results - Using mouse carotid arteries maintained in organ culture for 3 days, we detected increased gelatin zymographic activity of matrix metalloproteinase ( MMP)- 2 ( 168 +/- 13%, P < 0.05) in vessels kept at low intraluminal pressure ( 10 mm Hg) compared with vessels at 80 mm Hg ( 100%), whereas in vessels maintained at high pressure ( 150 mm Hg), both MMP- 2 and MMP- 9 activity was induced ( 182 +/- 32%, P < 0.05, and 194 +/- 21%, P < 0.01, respectively). MMPs were detected in endothelial and smooth muscle cells by immunohistochemistry and in situ gelatin zymography. In vessels at 150 mm Hg, MMP activation was associated with a shift in the pressure- diameter curve toward greater distensibility ( P < 0.01) compared with vessels at 80 mm Hg. However, distensibility was not altered in vessels at 10 mm Hg, in which only activated MMP- 2 was detected. The role of MMPs in high pressure - induced vessel distensibility was confirmed by use of the MMP inhibitor FN- 439, which prevented the shift in the pressure- diameter relationship. Furthermore, in carotid arteries from MMP- 9 - deficient mice, the pressure- dependent increase in MMP- 2 and in situ gelatinolytic activity were maintained, but the upward shift in the pressure- diameter curve was abolished. Conclusions - MMP- 9 seems to play a key role in the early stages of hypertensive vascular remodeling.