Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model

Abstract

Background - The matrix-degrading activity of matrix metalloproteinases (MMPs), required for cell migration and general tissue reshaping, is thought essential for pathological arterial remodeling in atherosclerosis and restenosis. Methods and Results - We triggered remodeling of the carotid artery in C57BL/6 mice by blood flow cessation to study the relationship with gelatinases MMP-9 and MMP-2. Ligated and contralateral carotid arteries from ligated and sham-operated mice were harvested fresh, for biochemical analyses, or were perfusion-fixed, for histological studies, at 0, 1, 3, 7, 14, and 28 days after ligation. An early statistically significant (P < 0.01) 4- to 5-fold increase in MMP-9 expression detected by SDS-PAGE zymography and Western blotting in tissue homogenates of ligated carotid arteries 1 day after flow cessation was maintained through day 7, after which expression gradually fell. Maximal MMP-9 levels were higher than MMP-2 levels, which became significantly increased 7 days after ligation. Proliferating cells, identified by bromodeoxyuridine incorporation, were detectable at day 1 in the adventitia and subsequently throughout the wall. Neointima was visible in 3-day specimens of ligated arteries. Suggested by morphology and predicted by theoretical considerations, maximal MMP-9 expression coincided with cell migration into the neointima, supporting its enabling role. Morphological measurements also demonstrated positive lumen remodeling up to 7 days after ligation. Conclusions - MMP-9 induction is associated with the formation of intimal hyperplasia and does not require frank mechanical injury. Our data also show that a significant increase in MMP-9 expression preceded the positive geometrical remodeling of arteries, suggesting a potentially beneficial role for this matrix-degrading enzyme.