Smooth muscle cells healing atherosclerotic plaque disruptions are of local, not blood, origin in apolipoprotein E knockout mice
Smooth muscle cells healing atherosclerotic plaque disruptions are of local, not blood, origin in apolipoprotein E knockout mice
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DOI：
10.1161/circulationaha.107.722355
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发表时间：
2007-10-30
期刊：
影响因子：
37.8
通讯作者：
Falk, Erling
中科院分区：
文献类型：
--
作者：
Bentzon, Jacob F.;Sondergaard, Claus S.;Falk, Erling
背景-动脉粥样硬化斑块中斑块破裂和平滑肌细胞（SMC）介导的愈合的早期症状是常见的，但愈合SMC的来源尚不清楚。最近的研究表明，粘附在损伤部位的活化血小板从循环的骨髓来源的祖细胞中募集新生内膜SMC。在这里，我们分析了载脂蛋白E基因敲除后自发和机械斑块破裂后，这种机制对斑块愈合的贡献（apoE（-/-））小鼠。方法和结果-为了确定自发斑块破裂后SMC的起源，用来自增强型绿色荧光蛋白（eGFP）转基因apoE（-/-）的骨髓细胞重建经辐照的18月龄apoE（-/-）小鼠小鼠并在9个月后死亡时进行检查。广泛存在斑块出血，表明先前的斑块破裂，但未检测到骨髓来源的eGFP（+）SMC。为了在一个模型中研究愈合SMC的起源，该模型重现了人类斑块破裂和愈合的更多特征，我们开发了一种机械技术，该技术在apoE（-/-）小鼠中产生一致的斑块破裂、叠加血栓形成和SMC介导的斑块愈合。在用eGFP（+）apoE（-/-）骨髓细胞重建的辐射apoE（-/-）小鼠中以及在apoE（-/-）和eGFP（+）apoE（-/-）小鼠之间交叉移植的颈动脉分叉中产生机械斑块破坏。除了少数非移植衍生的SMC附近的吻合部位在1移植的颈动脉分叉，没有SMC起源于当地动脉段外被检测到在愈合plaques.Conclusions -动脉粥样硬化斑块破裂后愈合SMC完全来自当地动脉壁，而不是循环祖细胞在apoE（-/-）小鼠。
Background - Signs of preceding episodes of plaque rupture and smooth muscle cell ( SMC) - mediated healing are common in atherosclerotic plaques, but the source of the healing SMCs is unknown. Recent studies suggest that activated platelets adhering to sites of injury recruit neointimal SMCs from circulating bone marrow - derived progenitor cells. Here, we analyzed the contribution of this mechanism to plaque healing after spontaneous and mechanical plaque disruption in apolipoprotein E knockout (apoE(-/-)) mice.Methods and Results - To determine the origin of SMCs after spontaneous plaque disruption, irradiated 18-month-old apoE(-/-) mice were reconstituted with bone marrow cells from enhanced green fluorescent protein (eGFP) transgenic apoE(-/-) mice and examined when they died up to 9 months later. Plaque hemorrhage, indicating previous plaque disruption, was widely present, but no bone marrow - derived eGFP(+) SMCs were detected. To examine the origin of healing SMCs in a model that recapitulates more features of human plaque rupture and healing, we developed a mechanical technique that produced consistent plaque disruption, superimposed thrombosis, and SMC-mediated plaque healing in apoE(-/-) mice. Mechanical plaque disruption was produced in irradiated apoE(-/-) mice reconstituted with eGFP(+) apoE(-/-) bone marrow cells and in carotid bifurcations cross-grafted between apoE(-/-) and eGFP(+) apoE(-/-) mice. Apart from few non-graft-derived SMCs near the anastomosis site in 1 transplanted carotid bifurcation, no SMCs originating from outside the local arterial segment were detected in healed plaques.Conclusions - Healing SMCs after atherosclerotic plaque disruption are derived entirely from the local arterial wall and not circulating progenitor cells in apoE(-/-) mice.