Influence of Fluid Shear Stress on Matrix Metalloproteinase Production in Endothelial Cells

Arterial bifurcations are known to be common sites for formation of cerebral aneurysms. It has been reported that shear stress of more than 7 Pa under physiological conditions exerts on near the flow divider of the bifurcations. It is thus speculated that such high shear stress may induce production of matrix metalloproteinases (MMPs) in endothelial cells (ECs), leading to the aneurysm formation. However, the detailed mechanism is still unknown. In this study, we evaluated the effect of magnitude of shear stress on expressions of MMP- 2 and -9, known to degrade elastic fibers and associate with the early stage of formation of aneurysms. ECs isolated from human umbilical veins were exposed to shear stress of 2 Pa or 7 Pa for 24 hours using a parallel-plate flow chamber. After flow-exposure experiments, ECs were cultured with serumfree medium for 12 hours. Then, MMP-2 and -9 activities in the conditioned medium was detected by gelatin zymography. While activated MMP-2 expression did not change between 2Pa and 7Pa, pro MMP-2 activity increased with increasing the magnitude of shear stress. The level of pro MMP-9 activity also increased according to the increase in shear stress, and was significantly higher at 7 Pa compared to the static. These results suggest that higher shear stress near the flow divider at bifurcation of cerebral arteries may enhance degradation of elastic fibers in vessel walls, possibly leading to formation of cerebral aneurysms.