权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The mechanism of intimal hyperplasia in vein graft

移植静脉内膜增生的机制

基本信息

批准号：
21591625
负责人：
UCHIDA Hisashi
金额：
$ 2.91万
依托单位：
Asahikawa Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21591625/
关键词：
血管平滑筋細胞 MMP-2 内膜肥厚低酸素インテグリン MMP2 HIF1α αvβ3インテグリン

项目摘要

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.

许多研究表明，基质金属蛋白酶在离体平滑肌细胞（SMC）迁移和动物损伤模型中的新生内膜增生（NH）病变形成中起重要作用。本研究旨在证明MMP-2在动静脉（AV）通路建立后的早期NH病变形成中具有关键作用。方法和结果：为了确定MMP-2对AV入路建立后早期NH病变形成至关重要，我们通过以端侧方式将颈总动脉与颈外静脉吻合来在小鼠体内建立AV瘘。3周后，与野生型MMP-2+/+小鼠相比，MMP-2-/-小鼠具有显著更少的吻合NH损伤形成，证实MMP-2活性确实对AV瘘背景下的早期新生内膜增生至关重要。明胶-底物酶谱分析显示，组织中MMP-2原和活化MMP-2的水平显著升高。MMP-2-/-小鼠在动静脉瘘形成后没有MMP-2活性。MMP-2-/-组MMP-9表达无代偿性增加。我们还证明，与人类对应物一样，小鼠NH病变主要是SMC（SM特异性α-肌动蛋白免疫染色）和最少量的巨噬细胞（Mac-3免疫染色）。体外培养的SMC在缺氧条件下，整合素αv、β3和MMP-2表达上调。这些分子之间似乎有某种联系。结论：早期由于吻合口新生内膜增生导致的原发性AV通路失败与MMP-2依赖性SMC迁移增加有关。AV瘘小鼠模型证实了这种相关性，该模型显示MMP-2-/-小鼠中吻合口新生内膜病变形成显著少于MMP-2+/+小鼠。