Objective— Although matrix metalloproteinase-9 (MMP-9) has been implicated in atherosclerotic plaque instability, the exact role it plays in the plaque development and progression remains largely unknown. We generated apolipoprotein E (apoE)–deficient (apoE^−/−) MMP-9–deficient (MMP-9^−/−) mice to determine the mechanisms and the main cell source of MMP-9 responsible for the plaque composition during accelerated atherosclerotic plaque formation.

Methods and Results— Three weeks after temporary carotid artery ligation revealed that while on a Western-type diet, apoE^−/− MMP-9^−/− mice had a significant reduction in intimal plaque length and volume compared with apoE^−/− MMP-9^+/+ mice. The reduction in plaque volume correlated with a significantly lower number of intraplaque cells of resident cells and bone marrow–derived cells. To determine the cellular origin of MMP-9 in plaque development, bone marrow transplantation after total-body irradiation was performed with apoE^−/− MMP-9^+/+ and apoE^−/− MMP-9^−/− mice, which showed that only MMP-9 derived from resident arterial cells is required for plaque development.

Conclusions— MMP-9 is derived from resident arterial cells and is required for early atherosclerotic plaque development and cellular accumulation in apoE^−/− mice.