模拟失重所致动脉区域特异性重建中动脉记忆效应的研究

Arterial remodeling is an adaptative response of artery to different environmental stresses. But the mechanisms of vascular remodeling, which are helpful to understand the adaptative response of artery to different environmental stresses, are still not fully understood until now. In our previous works, we found that hindlimb unweighting simulated microgravity can result in regional specific arterial remodeling, but daily 1h intermittent artificial gravity (IAG) as a countermeasure can prevent this arterial differential remodeling. In our recent works, we established an organ culture system in which rat common carotid artery, held at in- vivo length, can be perfused and pressurized at varied flow and pressure for 7 days. In arteries perfused at 150 mmHg for 3 days, we found an augmentation of c-fibronectin expression and an increase in Ang II production detected in the perfusion fluid. However, the enhanced c-fibronectin expression and increased Ang II production that might occur due to a sustained high perfusion pressure alone were fully prevented by daily restoration to 80 mmHg for a short duration. These surprised findings from in-vivo and ex-vivo experiments have indicated that artery may keep or recover to their original function and structure in an altered environment by intermittent recovery to its original environment. We just named this kind of ability as “arterial memory effect” which is different with homeostasis. In this work, different animal models (hindlimb unweighting simulated microgravity rat model, intermittent artificial gravity model) and artery culture model will be used to induce arterial remodeling, and intermittent countermeasures will be applied to recover the remodeling changes. The differences of arterial function and structure among different experiments will be compared by several methods in different levels. And the differences in related pathway will also be compared. By analysis of these differences, we may confirm this “arterial memory effect”, and find the key regulatory points of “arterial memory effect”. By the knowledge we learned from this work, we may find the new methods or new drug target to change the steps of arterial remodeling.

动脉重建是环境条件变化时动脉结构和功能发生适应性改变的过程，其机理对理解心血管系统在各种环境下的适应有着非常重要的意义，但目前尚缺乏全面深入认识。在前期工作中，我们发现模拟失重可导致大鼠动脉发生区域特异性重建，而每天1小时的间断人工重力对抗即可防止部分动脉重建的发生；在进一步的动脉培养实验中，我们惊奇地观察到，高压灌流培养期间，每天仅1小时恢复正常灌流压即可防止高压灌流培养所致动脉的变化。我们暂将动脉的这种在异常环境中通过短暂恢复正常环境条件即能保持或恢复正常功能与结构的能力称之为“记忆效应”。其有别于动脉的稳态，类似于记忆合金材料在温度变化后产生形变，在温度恢复到原温度时能够恢复之前形状的性质。本项申请拟利用模拟失重大鼠模型与间断人工重力干预模型，结合动脉变压培养模型，采用比较研究手段，以确立模拟失重动脉重建中的动脉记忆效应、探讨其发生机理并初筛其调控分子。

航天微重力环境所致动脉系统重建是航天后立位耐力不良发生的重要机制之一，阐明其变化及其机理并针对性发展对抗措施对保障航天人员健康与维护航天人员工作能力具有重要意义，同时亦有助于全面认识动脉重建的变化与机理。我们发现模拟失重可导致大鼠动脉发生区域特异性重建，而每天1小时的间断1G重力对抗可防止部分动脉重建的发生；我们暂将动脉的这种在异常环境中通过短暂恢复正常环境条件即能保持或恢复正常功能与结构的能力称之为“ 记忆效应”。其有别于动脉的稳态，类似于记忆合金材料在温度变化后产生形变，在温度恢复到原温度时能够恢复之前形状的性质。阐明模拟失重下动脉记忆效应相关变化及其机理，有助于了解间断人工重力作为微重力影响对抗措施的可行性，也可能为动脉重建提供新的认识。本工作主要采用模拟失重大鼠模型与间断人工重力模型开展研究，首先通过功能与形态学方法，探讨了模拟失重下动脉记忆效应发生的时间特征与部位特征；在此基础上，选择脑动脉、肠系膜动脉与股动脉比较了一氧化氮系统、肾素-血管紧张素系统、脂筏/穴样凹陷与整合素等关键分子的核酸水平与蛋白表达的变化，以探讨可能与动脉记忆效应相关的信号通路；在前述工作基础上，选用模拟失重组大鼠、间断人工重力组大鼠与对照组大鼠脑动脉、股动脉和肠系膜动脉开展了基因芯片测序工作。本项工作结果显示，模拟失重大鼠动脉发生了区域特异性重建，不同模拟失重时间所致动脉区域特异性重建具有一定差异，不同时长的1G间断人工重力可以完全恢复部分动脉在不同时长模拟失重下的动脉重建，但亦有动脉在不同时长1G间断人工重力干预下不能完全恢复。动脉重建与间断人工重力对抗作用涉及多个信号通路，通过基因芯片亦发现了新的可能信号通路。本工作结果提示，在模拟失重大鼠的多个动脉均存在动脉记忆效应，但模拟失重不同时间与不同动脉间，动脉记忆效应存在差异，间断人工重力对抗微重力所致动脉区域特异性重建具有应用价值。