钙离子激活型钾离子通道KCa3.1在血流动力学诱导的颅内动脉瘤发生的机制研究

Aneurysmal subarachnoid hemorrhage is one of the main causes of death and disability in the worldwide. However, the mechanism of cerebral aneurysm initiation is not clear right now. The future research should focus on the pathology behind the initiation and development of aSAH and emphasize on the molecular mechanism to discover the possible treatment options and reduce the progression of aSAH. The treatment will ultimately reduce the morbidity and mortality of aSAH and improve the overall quality of life for patient.Our preliminary study demonstrated that blockade of the KCa3.1 mitigates cerebral aneurysmal remodeling in rat model. Previous study also revealed that linear shear stress could upregulate the expression of KCa3.1 mRNA in endothelium cells. Accordingly, those results indicate that KCa3.1 may play an important role in the function of the endothelium cell and the vascular remodeling. This in-vitro and in-vivo study aims to explore the pathway of transducing the abnormal mechanical stress to the biological responses in the artery wall mediated by KCa3.1, and trying to clarify the biological mechanism of the cerebral aneurysm initiation by the endothelium cell injury through the abnormal mechanical stress induced KCa3.1 activation. This study will be helpful to the future noninvasive or drug therapy development of cerebral aneurysm management.

颅内动脉瘤破裂导致的蛛网膜下腔出血是全世界范围内导致病患致死致残的最主要原因之一，然而颅内动脉瘤的自然病史及发生机制尚未清晰，因此亟待明确其发病的生物和力学机制并探索新的治疗靶点，以预防或逆转动脉瘤的转归，降低该病残死率，提高生活质量。我们前期的预实验结果表明，在单纯血流动力学诱导的大鼠颅内动脉瘤模型中，特异性阻断KCa3.1通道可以显著减少大鼠在前交通动脉复合体处的动脉瘤样重构。亦有研究发现KCa3.1 mRNA在加载线性剪切应力后表达上调，说明KCa3.1在血流异常的情况下可能对血管适应性重塑起着重要作用。本研究通过体外细胞培养及动物模型体内验证两种方法，探讨KCa3.1在异常血流力学环境下将机械应力信号转换为生物反应的可能信号通路，提出由KCa3.1介导的机械应力所导致血管内皮损伤机制，并进一步形成动脉瘤的可能分子生物学机制，为探索无创治疗颅内动脉瘤有效的生物学靶点提供重要参考。