Degradation of Glycocalyx and Multiple Manifestations of Endothelial Dysfunction Coincide in the Early Phase of Endothelial Dysfunction Before Atherosclerotic Plaque Development in Apolipoprotein E/Low-Density Lipoprotein Receptor-Deficient Mice
Degradation of Glycocalyx and Multiple Manifestations of Endothelial Dysfunction Coincide in the Early Phase of Endothelial Dysfunction Before Atherosclerotic Plaque Development in Apolipoprotein E/Low-Density Lipoprotein Receptor-Deficient Mice
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DOI：
10.1161/jaha.118.011171
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发表时间：
2019-03-19
影响因子：
5.4
通讯作者：
Chlopicki, Stefan
中科院分区：
文献类型：
--
作者：
Bar, Anna;Targosz-Korecka, Marta;Chlopicki, Stefan
背景-内皮依赖性血管扩张功能受损、内皮通透性增加和糖基化均是内皮功能障碍的重要病理生理成分。然而，目前尚不清楚在动脉粥样硬化中，糖肾盏损伤是否先于内皮功能障碍的其他特征，或者这些事件是否一致。方法与结果-在这里，我们证明了在4-8周龄的载脂蛋白E/低密度脂蛋白受体缺陷小鼠中，在动脉粥样硬化斑块形成之前的阶段，乙酰胆碱诱导的血管扩张受损，主动脉中一氧化氮的产生减少，内皮通透性增加；然而，股动脉的血流介导的扩张完全被保留。在4周龄的小鼠中，8周龄的小鼠糖萼覆盖率降低，血管内皮细胞硬度增加，而糖萼长度显著缩短。早期的内皮功能改变还表现为血浆中糖基化断裂生物标记物(Endocan)、内皮炎症生物标记物(可溶性血管细胞黏附分子1)、血管通透性增加(血管生成素2)以及止血改变(组织纤溶酶原激活物和纤溶酶原激活物抑制物1)。在28周龄的小鼠中，在晚期动脉粥样硬化斑块发展阶段，与动脉粥样硬化前斑块阶段相比，内皮功能障碍的几乎所有其他特征都发生了类似程度的变化。例外情况是，在主动脉和头臂动脉出现乙酰胆碱诱导的血管收缩，股动脉的血流介导的血管扩张受损，糖萼长度和覆盖率进一步缩短，伴随着内皮通透性的进一步增加。结论--总结--即使在动脉粥样硬化斑块形成之前的早期阶段，内皮功能障碍也是一个复杂的多因素反应，以前还没有意识到。
Background-The impairment of endothelium-dependent vasodilation, increased endothelial permeability, and glycocalyx degradation are all important pathophysiological components of endothelial dysfunction. However, it is still not clear whether in atherosclerosis, glycocalyx injury precedes other features of endothelial dysfunction or these events coincide.Methods and Results-Herein, we demonstrate that in 4- to 8-week-old apolipoprotein E/low-density lipoprotein receptor-deficient mice, at the stage before development of atherosclerotic plaques, impaired acetylcholine-induced vasodilation, reduced NO production in aorta, and increased endothelial permeability were all observed; however, flow-mediated dilation in the femoral artery was fully preserved. In 4-week-old mice, glycocalyx coverage was reduced and endothelial stiffness was increased, whereas glycocalyx length was significantly decreased at 8 weeks of age. Early changes in endothelial function were also featured by increased plasma concentration of biomarkers of glycocalyx disruption (endocan), biomarkers of endothelial inflammation (soluble vascular cell adhesion molecule 1), increased vascular permeability (angiopoietin 2), and alterations in hemostasis (tissue plasminogen activator and plasminogen activator inhibitor 1). In 28-week-old mice, at the stage of advanced atherosclerotic plaque development, impaired NO production and nearly all other features of endothelial dysfunction were changed to a similar extent, compared with the preatherosclerotic plaque phase. The exceptions were the occurrence of acetylcholine-induced vasoconstriction in the aorta and brachiocephalic artery, impaired flow-mediated vasodilation in the femoral artery, and further reduction of glycocalyx length and coverage with a concomitant further increase in endothelial permeability.Conclusions-In conclusion, even at the early stage before the development of atherosclerotic plaques, endothelial dysfunction is a complex multifactorial response that has not been previously appreciated.