Vascular remodeling during aging and atherosclerosis is characterized by the thickening of the vessel wall, especially the intimal hyperplasia involving smooth muscle cells (SMC) migration and proliferation. Matrix metalloproteinase-2 (MMP-2), a proteolytic enzyme that degrade type IV collagen, facilitates SMC migration. We have studied the expression of MMP-2 in the vessel wall of young and old rats and human aortic wall and atherosclerotic lesions. In aortae of old rats, we observed that enhanced immunohistochemical staining of MMP-2, and enhanced activity by the in situ zymographic technique, were regionally localized to the intima, which increases 5-fold in thickness between 6 and 30 month. Total MMP-2 protein in the aortic wall of old rats (Western blot) was 8-fold increased over that of young rats (0.166+-0.032 vs. 0.020+-0.006, p<0.01). In unstimulated SMC isolated from the two age groups, MMP-2 production was not different. However, after stimulation by cytokines (10 ng/ml each for 24 h), MMP-2 production by SMC of old rats was greater than in young: old/young % MMP-2 was 120.1% (latent, p<0.01) and 154.17% (activated, p<0.01), following IL-1?; was 117.4% (latent, p<0.01) and 142.5% (activated, p<0.01), following TNF-alpha; and was 103.9% (latent, p>0.05), 111.3% (activated, p<0.05) following TGF-beta. In human aortic atherosclerosis, a greater amount of MMP-2 is present in fatty streaks and atherosclerotic plaques as compared to normal regions of the aorta. Immunoblotting analysis showed that MMP-2 was expressed in atherosclerotic plaque > fatty streak > normal aortic wall in a ratio of about 4:2:1. Zymograms showed that both forms (active and latent) of MMP-2 increased in the atherosclerotic plaques. Localization of MMP-2 in the fibrous cap of plaque may contribute to rupture of an atherosclerotic lesion. Furthermore, an enhanced expression of p53 and ICE proteins in the atherosclerotic lesion and presence of apoptotic cells in the rim of central lipid core, may also encourage the ulceration and rupture of the plaque. Thus, SMC from old rats are more sensitive to cytokine induction of MMP-2 than SMC from young rats, suggesting a mechanism that leads to in vivo accumulation of this enzyme in the aortic wall with adult aging, and a potential role for MMP-2 in age-associated remodeling of the vasculature. MMP-2 may have a role in the formation and progression of atherosclerotic lesion, and may be involved in clinical complications of atherosclerosis, such as fissure and rupture, leading to thrombosis.
