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.