1 Jagiellonian University Jagiellonian Centre for Experimental Therapeutics Krakow Poland.
3 Jagiellonian University Medical College Faculty of Medicine Chair of Pharmacology Krakow Poland.
J Am Heart Assoc. 2019 Mar 19;8(6):e011171. doi: 10.1161/JAHA.118.011171.
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.
内皮依赖性血管舒张功能障碍、内皮通透性增加和糖萼降解都是内皮功能障碍的重要病理生理组成部分。然而，在动脉粥样硬化中，糖萼损伤是否先于其他内皮功能障碍特征发生，或者这些事件是否同时发生，目前仍不清楚。
在此，我们证明在 4 至 8 周龄的载脂蛋白 E/低密度脂蛋白受体缺陷型小鼠中，在动脉粥样硬化斑块形成之前的阶段，观察到乙酰胆碱诱导的血管舒张受损、主动脉中一氧化氮（NO）生成减少和内皮通透性增加；然而，股动脉的血流介导扩张完全保留。在 4 周龄的小鼠中，糖萼覆盖率降低，内皮僵硬度增加，而在 8 周龄时，糖萼长度显著减少。内皮功能的早期变化还表现为糖萼破坏的生物标志物（内脂素）、内皮炎症的生物标志物（可溶性血管细胞黏附分子 1）、血管通透性增加的生物标志物（血管生成素 2）和止血改变（组织型纤溶酶原激活物和纤溶酶原激活物抑制剂 1）的血浆浓度升高。在 28 周龄的小鼠中，在进展性动脉粥样硬化斑块形成的阶段，与动脉粥样硬化前斑块阶段相比，NO 生成减少和几乎所有其他内皮功能障碍特征都发生了类似程度的改变。例外的是主动脉和头臂动脉中乙酰胆碱诱导的血管收缩、股动脉血流介导的血管扩张受损以及糖萼长度和覆盖率进一步降低，同时内皮通透性进一步增加。
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种以前未被认识的复杂多因素反应。
