The mechanism of intimal hyperplasia in vein graft

许多研究人员已经证明，在动物损伤模型中，MMPs在平滑肌细胞(SMC)的体外迁移和新生内膜增生(NH)病变的形成中起重要作用。本研究旨在证明基质金属蛋白酶-2在动静脉通路建立后早期NH病变的形成中起关键作用。方法和结果：为了确定基质金属蛋白酶-2在建立动静脉通路后早期NH病变形成中的关键作用，我们通过将颈总动脉与颈外静脉端侧吻合的方式建立了一个动静脉瘘。3周后，与野生型MMP2+/+小鼠相比，MMP2-/-小鼠吻合口NH病变的形成明显减少，证实了MMP2活性确实是房室瘘早期新生内膜增生的关键。明胶底物酶谱显示组织中原-基质金属蛋白酶-2和活化基质金属蛋白酶-2的表达水平明显升高。同时发现，MMP2-/-MICE无MMP2活性，减少了房室瘘的形成。这些基质金属蛋白酶-2-/-基质金属蛋白酶-9的表达没有代偿性增加。我们还证明，与人类的相应病变一样，小鼠的NH病变主要是SMCs(SM特异性α-肌动蛋白免疫染色)，并有少量的巨噬细胞(Mac-3免疫染色)。在体外，在低氧条件下培养的细胞，整合素MMPv、α-3和β-2表达上调。在它的表达上，似乎这些分子之间有一些关系。结论：吻合口新生内膜增生所致的早期房室引流失败与依赖于基质金属蛋白酶-2的SMC迁移增加有关。这种关联在动静脉瘘小鼠模型中得到了证实，该模型显示，与MMP2+/+小鼠相比，MMP2-/-小鼠吻合口新生内膜病变的形成明显减少。

Many investigators have demonstrated that MMPs are important in smooth muscle cell (SMC) migration ex vivo and in neointimal hyperplasia (NH) lesion formation in animal model of injury. This study aim to demonstrate that MMP-2 have a critical role in the early NH lesion formation after arteriovenous (AV) access creation. Methods and Results : To determine MMP-2 is critical to early NH lesion formation after AV access creation, we created an AV fistula in mice by anastomosing the common carotid artery to the external jugular vein in an end-to-side fashion. After 3 weeks, MMP-2-/-mice have significantly less anastomotic NH lesion formation compared to the wild-type MMP-2+/+ mice confirming that MMP-2 activity is indeed critical to early neointimal hyperplasia in the setting of AV fistulae. And there is significant increase in the tissue levels of pro-MMP-2 and activated MMP-2 based the gelatin-substrate zymography. Also foundMMP-2-/-micehad noMMP-2 activityfonollowing AV fistula creation. These MMP-2-/-wemice did not have compensatory increase in the expression of MMP-9. We also demonstrated that like the human counterpart, the mouse NH lesion is predominantly SMCs (SM specific α-actin immunostaining) with minimal number of macrophages (Mac-3 immunostaining). In vitro, integrin αv, β3, and MMP-2 was up-regulated in SMC, when the cells cultured under hypoxic conditions. It seemed to have some relations between these molecules at its expressions. Conclusions : Ewasarly primary AV access failure due to anastomotic neointimal hyperplasia is associated with increased MMP-2-dependent SMC migration. This association is confirmed with the AV fistula mouse model, which demonstrated a significantly less anastomotic neointimal lesion formation in MMP-2-/-mice as compared to MMP-2+/+ mice.