Role of Matrix Metalloproteinase in Vascular Remodeling

虽然已经证明基质金属蛋白酶（MMPs）在动脉粥样硬化和再狭窄的动脉重塑中起重要作用，但目前尚不清楚哪个MMP参与了哪个过程。为了明确MMP-2在动脉重塑中的作用，我们评估了MMP-2基因靶向缺失对小鼠颈动脉血流停止后血管重塑的影响。方法与结果将野生型和mmp -2缺陷小鼠的左颈总动脉在其分叉的近端结扎，然后在特定时间点对动物进行形态学和生化研究。明胶酶谱法和实时荧光定量RT-PCR观察野生型小鼠结扎颈动脉中MMP-2活性和mRNA水平升高。在结扎后2周和4周，mmp -2缺失小鼠的内膜增生明显少于野生型小鼠。与野生型小鼠相比，从mmp -2缺失小鼠的主动脉中提取的动脉外植体显示，平滑肌细胞（SMC）的迁移受到抑制。在mmp -2缺陷小鼠培养的SMCs中，化学引诱剂通过重建基底膜屏障的侵袭显著减少，尽管在对照组和mmp -2缺陷小鼠之间，SMCs通过过滤器的迁移或增殖反应没有观察到差异。结论在小鼠颈动脉血流停止模型中，MMP-2主要通过降解和破坏细胞周围的细胞外基质蛋白和基底膜屏障，使SMC从介质迁移到内膜，从而促进内膜增生。

BackgroundAlthough it has been demonstrated that matrix metalloproteinases (MMPs) play an important role in the arterial remodeling in atherosclerosis and restenosis, it is not clear which MMP is involved in which process. To define the role of MMP-2 in arterial remodeling, we evaluated the influence of the targeted deletion of the MMP-2 gene on vascular remodeling after flow cessation in the murine carotid arteries.Methods and ResultsThe left common carotid arteries of wild-type and MMP-2-deficient mice were ligated just proximal to their bifurcations, and the animals were then processed for morphological and biochemical studies at specific time points. MMP-2 activity and mRNA levels increased in ligated carotid arteries of wild-type mice on the basis of observation by gelatin zymography and quantitative real-time RT-PCR. There was significantly less intimal hyperplasia in MMP-2-deficient mice at 2 and 4 weeks after ligation than there in wild-type mice. Arterial explants from the aorta of MMP-2-deficient mice showed that smooth muscle cell (SMC) migration was inhibited in comparison with wild-type mice. The chemoattractant-directed invasion through a reconstituted basement membrane barrier was significantly reduced in cultured SMCs derived from MMP-2-deficient mice, although no difference was observed in SMC migration across the filter or in proliferative response between the control and MMP-2-deficient mice.ConclusionsIn a mouse carotid artery blood flow cessation model, MMP-2 contributes to intimal hyperplasia mainly through the SMC migration from the media into the intima by degrading and breaching the extracellular matrix proteins surrounding each cell and the basement membrane barrier.