Paracrine effect of vascular smooth muscle cells in the prevention of aortic aneurysm formation
Paracrine effect of vascular smooth muscle cells in the prevention of aortic aneurysm formation
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DOI：
10.1067/mva.2002.127347
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发表时间：
2002-11-01
影响因子：
4.3
通讯作者：
Becquemin, JP
中科院分区：
文献类型：
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作者：
Allaire, E;Muscatelli-Groux, B;Becquemin, JP
目的：观察腹主动脉瘤（AAAs）血管平滑肌细胞（VSMC）密度降低的中膜炎症和弹性蛋白溶解。相反，弹性蛋白和VSMCs在狭窄性动脉粥样硬化病变的非炎症介质中保留。我们在大鼠AAA模型中测试了VSMCs对炎症和蛋白质水解具有保护作用的假设，其中内侧弹性蛋白降解是由炎症和基质金属蛋白酶驱动的。方法：将脱细胞的豚鼠主动脉（异种移植）原位植入fisher -344大鼠体内，并以与受体相同的大鼠VSMCs悬液为种子，或注入培养基作为对照。植入后8周定量培养基直径和弹性蛋白。在植入后1周和2周，分析炎症、基质金属蛋白酶（AIMP）和基质金属蛋白酶组织抑制剂（TIMP）的表达。添加VSMC可阻止AAA形成（平均+/-标准差直径增加：198.2% +/- 106.6% vs 35.3% +/- 17.8%, P = 0.009）、弹性蛋白降解和单核巨噬细胞浸润减少。MMP-2、MMP-9、TIMP-1、TIMP-2和TIMP-3的逆转录聚合酶链反应、酶谱分析和反向酶谱分析表明，添加VSMCs后，蛋白水解-抗蛋白水解平衡发生了变化。在外膜中观察到转录变化，尽管种子VSMCs仍位于内膜。结论：VSMCs对外膜具有旁分泌作用，参与抗炎症和蛋白水解的动脉壁稳态。这种保护机制的失效导致了AAA的形成。了解VSMC保护作用的分子机制可能为动脉瘤和斑块破裂的治疗提供新的途径。
Objective: Inflammation and elastinolysis are observed in the media of abdominal aortic aneurysms (AAAs) where vascular smooth muscle cell (VSMC) density is decreased. In contrast, elastin and VSMCs are preserved in the noninflammatory media of stenotic atherosclerotic lesions. We have tested the hypothesis that VSMCs exert a protective effect against inflammation and proteolysis in a model of AAA in rats, in which medial elastin degradation is driven by inflammation and matrix metalloproteinases.Method: Decellularized guinea pig aortas (xenografts) were implanted orthotopically into Fischer-344 rats and seeded with a suspension of rat VSMCs syngeneic to the rat recipient, or were infused with culture medium as a control. Diameter and elastin in the media were quantified 8 weeks after implantation. Inflammation, matrix metalloproteinase (AIMP) and tissue inhibitor of matrix metalloproteinase (TIMP) expression were analyzed 1 and 2 weeks after implantation.Results. VSMC addition prevented AAA formation (mean +/- standard deviation diameter increase: 198.2% +/- 106.6% vs 35.3% +/- 17.8%, P = .009), elastin degradation, and decreased infiltration by monocyte-macrophages. Reverse-transcriptase polymerase chain reaction, zymography and reverse zymography for MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP-3 demonstrated a shift of the proteolytic-antiproteolytic balance upon addition of VSMCs. Transcriptional changes were observed in the adventitia, although seeded VSMCs remained located in the intima.Conclusions: VSMCs exert a paracrine effect on the adventitia that participate in artery wall homeostasis against inflammation and proteolysis. Failure of this protective mechanism results in AAA formation. The understanding of the molecular mechanisms underlying VSMC protective effect may represent a new approach in the treatment of aneurysm and plaque rupture.