Role of Matrix Metalloproteinase in Vascular Remodeling

尽管已证实基质金属蛋白酶(MMPs)在动脉粥样硬化和再狭窄的动脉重塑中起重要作用，但目前还不清楚哪些MMPs参与了这一过程。为了明确基质金属蛋白酶-2在动脉重构中的作用，我们评价了靶向缺失基质金属蛋白酶-2基因对小鼠颈总动脉血流停止后血管重构的影响。方法与结果结扎野生型和基质金属蛋白酶-2基因缺陷小鼠左侧颈总动脉分叉近端，在特定时间点对动物进行形态和生化研究。明胶酶谱和实时定量RT-PCR检测结果显示，野生型小鼠颈总动脉结扎后，基质金属蛋白酶-2活性和mRNA水平均升高。在结扎后2周和4周，基质金属蛋白酶-2缺陷小鼠的内膜增生明显少于野生型小鼠。与野生型小鼠相比，基质金属蛋白酶-2基因缺陷小鼠的动脉外植体显示平滑肌细胞(SMC)的迁移受到抑制。MMP2缺陷小鼠培养的SMC通过重组基底膜屏障的趋化侵袭显著减少，而对照组和MMP2缺陷小鼠的SMC迁移和增殖反应无明显差异。结论在小鼠颈动脉血流停止模型中，MMP2主要通过降解和破坏细胞周围细胞外基质蛋白和基底膜屏障，使SMC从中膜迁移到内膜而导致内膜增生。

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.