大鼠无创动脉僵硬度评价方法的建立及在失重致血管硬化研究中的应用

Arterial stiffness (AS) is one of the earliest detectable indicators for the structural and functional abnormality within the arterial wall. It is also an independent predictor strong predictor of cardiovascular diseases. A new study has discovered that spaceflight significantly increased stiffness of carotid artery. However, currently, there is lack of a reliable noninvasive method for evaluating systemic AS change induced by microgravity, thus the degree, characteristics of distribution and dynamic change of influences of microgravity on the stiffness of the arterial tree are not clear, and the underlying mechanism remains unclear as well. In previous studies, based on ultrasonic Doppler, we have completed the establishment and verification of a new method for measuring pulse wave velocity in rats, in which we put forward a new method for propagation distance calculation. This laid a good foundation for the establishment of the methodology for noninvasive AS evaluation in rats. By this method, we found that simulated microgravity preferentially stiffens arteries above heart but doesn’t change the stiffness of arteries below heart level; we also discovered that the endothelium dysfunction may play an important role act as one possible mechanism by which microgravity induces arterial stiffening. This project is designed to complete the establishment of the methodology for noninvasive AS evaluation in rats, to find out the degree, characteristics of distribution and dynamic change of influences of microgravity on the stiffness of the arterial tree, and investigate the roles of endothelium dysfunction especially the Akt-eNOS-NO and ERK1/2-ET-1 signaling pathways in the microgravity-induced arterial stiffening. This project can provide a reliable method for the evaluation of arterial elasticity in rat models, may provide new experimental evidence for the study of microgravity on vascular functions, may also help to produce a new prevention strategy for arterial stiffening.

动脉僵硬度（AS）是动脉管壁发生结构和功能异常最早的可检测指标之一，是一项心血管疾病的独立预测指标。新近发现失重可显著加速颈部血管硬化。然而目前对于大鼠模型AS的无创评价尚缺乏可靠、统一的方法。失重对全身AS的影响程度、分布特点、动态变化及机制尚不明确。我们前期基于超声多普勒技术提出并验证了大鼠脉搏波传播速度新的测算方法，为大鼠模型AS无创评价方法的建立奠定了良好基础；基于此，我们发现失重会导致心脏水平以上AS的增加，而不影响心脏水平以下；发现内皮功能障碍可能在失重致血管硬化中发挥了重要作用。本项目拟进一步完善大鼠AS无创评价方法的建立，明确失重对全身AS的影响规律，并探索内皮功能障碍，特别是舒血管通路Akt-eNOS-NO与缩血管通路ERK1/2-ET-1的失衡在其中的作用机制。本项目可提供一种可靠的大鼠模型动脉弹性评价方法，为失重影响血管功能研究提供新依据，为血管硬化的预防提供新思路。

动脉僵硬度是血管壁发生结构和功能异常最早的可检测指标，是心血管疾病及全因死亡风险的独立预测指标，而长期航天失重可加速血管硬化。但是，本领域存在三个重要难题悬而未决：广泛应用的大鼠模型尚无简便、可靠的无创动脉僵硬度测量方法；失重对机体全身动脉僵硬度的影响规律不明；失重致血管硬化的相关机制不清。针对性地，本项目采用超声多普勒技术，基于新提出的主动脉脉搏波传播速度测算方法，建立了一种无创大鼠动脉僵硬度评价新方法，并将其应用于模拟失重对全身血管硬化影响的研究中，以明确失重对动脉僵硬度影响的分布、程度以及动态变化规律等问题，并在此基础上，对失重致血管硬化的相关机制进行了探索研究。结果显示，新提出的基于超声多普勒主动脉脉搏波传播速度测量的大鼠动脉僵硬度检测新方法与有创导管法测量结果间的相关性和一致性较高，且优于传统方法，可为基础科研中大鼠模型动脉僵硬度的无创测量提供一种简便、可靠的新方法。本项目还揭示，模拟失重会引起大鼠心脏水平以上及以下大动脉的僵硬度的差异性改变，即导致心脏水平以上动脉硬化，而不显著影响心脏水平以下的大动脉僵硬度，并且此硬化是一个可逆过程。进一步，模拟失重会引起颈动脉内膜-中膜厚度和横截面积、胶原蛋白均明显增加，内皮依赖性血管舒张效应显著减弱。miR-582-5p和miR-380-3p作为潜在关键 miRNA可能参与了模拟失重致大鼠颈动脉僵硬度增加的调控。本项目研究团队分工明确，顺利完成研究内容，达到预期目的，取得了丰硕的科研成果，累及发表科研论文9篇，申请发明专利1项，培养博士后、硕士研究生各1名。本项目具有重要的科学意义及实用价值，可提供一种简便、可靠的大鼠模型动脉弹性评价新方法，有望为航天失重影响机体血管功能研究提供新依据，为航天员心血管保护提供新思路。