Contribution of macromolecular structure to the retention of low-density lipoprotein at arterial branch points
Contribution of macromolecular structure to the retention of low-density lipoprotein at arterial branch points
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DOI：
10.1161/circulationaha.107.754614
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发表时间：
2008-06-03
期刊：
影响因子：
37.8
通讯作者：
Balaban, Robert S.
中科院分区：
文献类型：
--
作者：
Kwon, Gina P.;Schroeder, Jamie L.;Balaban, Robert S.
背景-低密度脂蛋白（LDL）在动脉壁的细胞外沉积是动脉粥样硬化的重要早期步骤。该过程优先发生在动脉分支点，反映了脂蛋白-动脉壁相互作用的区域差异。在本研究中，我们表征了动脉壁胶原蛋白和弹性蛋白的亚微米微观结构，以评估其在局部低密度脂蛋白沉积中的潜在作用。方法和结果-通过2光子显微镜，我们利用胶原蛋白和弹性蛋白的固有光学特性来确定新鲜猪和鼠动脉中的动脉壁大分子微观结构。这种光学方法生成了独特的无损正面 3 维墙壁视图。发现胶原蛋白/弹性蛋白微观结构随动脉床的拓扑结构而变化。几乎融合的弹性蛋白表面层始终存在，但在动脉粥样硬化易感分支点处缺失，暴露出致密的胶原蛋白-蛋白聚糖复合物。在 LDL 结合研究中，这种管腔弹性蛋白层限制了 LDL 渗透，而分支处的缺失导致了广泛的 LDL 结合。此外，LDL 与蛋白多糖共定位，具有 S 形剂量依赖性（拐点，大约 130 mg LDL/dL）。离子强度和竞争阴离子研究与 LDL 与蛋白聚糖的初始相互作用一致，本质上是静电的。结论-这种光学切片方法提供了新鲜样品中动脉壁的稳健的 3 维胶原蛋白/弹性蛋白微结构。在动脉粥样硬化易感的血管分支点，管腔弹性蛋白屏障的缺失和致密胶原蛋白/蛋白聚糖基质的存在有助于增加 LDL 的保留。
Background-Extracellular deposition of low-density lipoprotein (LDL) in the arterial wall is an essential early step in atherosclerosis. This process preferentially occurs at arterial branch points, reflecting a regional variation in lipoprotein-arterial wall interactions. In this study, we characterized the submicron microstructure of arterial wall collagen and elastin to evaluate its potential role in regional LDL deposition.Methods and Results-With 2-photon microscopy, we used the intrinsic optical properties of collagen and elastin to determine the arterial wall macromolecular microstructure in fresh porcine and murine arteries. This optical approach generated unique nondestructive en face 3-dimensional views of the wall. The collagen/elastin microstructure was found to vary with the topology of the arterial bed. A nearly confluent elastin surface layer was present throughout but was missing at atherosclerosis-susceptible branch points, exposing dense collagen-proteoglycan complexes. In LDL binding studies, this luminal elastin layer limited LDL penetration, whereas its absence at the branches resulted in extensive LDL binding. Furthermore, LDL colocalized with proteoglycans with a sigmoidal dose dependence (inflection point, approximate to 130 mg LDL/dL). Ionic strength and competing anions studies were consistent with the initial interaction of LDL with proteoglycans to be electrostatic in nature.Conclusions-This optical sectioning approach provided a robust 3-dimensional collagen/elastin microstructure of the arterial wall in fresh samples. At atherosclerosis-susceptible vascular branch points, the absence of a luminal elastin barrier and the presence of a dense collagen/proteoglycan matrix contribute to increased retention of LDL.