Allaire Eric, Muscatelli-Groux Béatrice, Mandet Chantal, Guinault Anne-Marie, Bruneval Patrick, Desgranges Pascal, Clowes Alexander, Méllière Didier, Becquemin Jean-Pierre
CNRS UMR-A 7054, Centre de Recherches Chirurgicales, Créteil, France.
J Vasc Surg. 2002 Nov;36(5):1018-26. doi: 10.1067/mva.2002.127347.
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.
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 (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP) expression were analyzed 1 and 2 weeks after implantation.
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.
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.
在腹主动脉瘤（AAA）的中膜中可观察到炎症和弹性蛋白溶解，其中血管平滑肌细胞（VSMC）密度降低。相比之下，在狭窄性动脉粥样硬化病变的非炎症性中膜中，弹性蛋白和VSMC得以保留。我们在大鼠AAA模型中检验了以下假设，即VSMC对炎症和蛋白水解具有保护作用，在该模型中，中膜弹性蛋白降解由炎症和基质金属蛋白酶驱动。
将去细胞豚鼠主动脉（异种移植物）原位植入Fischer-344大鼠体内，并用与大鼠受体同基因的大鼠VSMC悬液接种，或注入培养基作为对照。植入后8周对中膜直径和弹性蛋白进行定量。植入后1周和2周分析炎症、基质金属蛋白酶（MMP）和基质金属蛋白酶组织抑制剂（TIMP）的表达。
添加VSMC可预防AAA形成（平均±标准差直径增加：198.2%±106.6%对35.3%±17.8%，P = 0.009）、弹性蛋白降解，并减少单核细胞 - 巨噬细胞浸润。对MMP-2、MMP-9、TIMP-1、TIMP-2和TIMP-3进行逆转录聚合酶链反应、酶谱分析和反向酶谱分析表明，添加VSMC后蛋白水解 - 抗蛋白水解平衡发生了变化。虽然接种的VSMC仍位于内膜，但在外膜中观察到了转录变化。
VSMC对外膜发挥旁分泌作用，参与动脉壁对抗炎症和蛋白水解的稳态维持。这种保护机制的失效会导致AAA形成。了解VSMC保护作用的分子机制可能代表了一种治疗动脉瘤和斑块破裂的新方法。
