脑血管痉挛(CVS)是自发性蛛网膜下腔出血(SAH)的特异并发症,与预后关系密切且具有重大治疗意义,迄今其关键病理生理环节(脑动脉平滑肌细胞过度去极化)的分子机制尚未阐明。ATP是重要的胞外信号分子和血管活性物质,也是致CVS因子之一,但其来源和作用机制不明。受平滑肌释放ATP现象及其受体P2X的研究进展启发,本课题组开展前期研究并发现分别抑制脑动脉平滑肌ATP和P2X均可使CVS显著缓解,故提出科学假设:脑动脉平滑肌ATP-P2X的整体功能在SAH后呈现出上调反应,从而以细胞过度去极化作为始发效应并导致CVS发生。项目将通过分子生物学、微透析并色谱分析、膜电位及离子通道门控、血管机能和脑血流动力学等从微观到宏观的研究方法,以明确平滑肌ATP-P2X在SAH后的活性变化及其在CVS中的作用机制。最终从肌源性信号角度为CVS的基础研究提供崭新视野和实质性创新,也为CVS的治疗提供实践指导。

Cerebral vasospasm (CVS), a severe complication of subarachnoid hemorrhage (SAH), determines the prognosis of this disease mostly, however, the key pathogenic molecule, resulting in excessive depolarization of cerebrovascular smooth muscle cells (CVSMCs) after SAH, is still unidentified. Adenosine triphosphate (ATP), a crucial extracellular signaling molecule as well as a vasoactive substances, is confirmed to cause CVS, but its origin and signaling pathway is remaining unknown. Most recently, a few studies found the local ATP release via CVSMCs, also termed as myogenic ATP, was sensitive to various diseases or stresses. Additionally, the myogenic ATP and its ionotropic receptor P2X (P2X1/X4), also expressed in CVSMCs, were shown to be involved in several vascular or neurological diseases. Based on the findings above and our interest in this area, preliminary studies showed that constricted cerebral artery has been dilated significantly through the inhibition of myogenic ATP and P2X after SAH. We therefore hypothesize myogenic ATP-P2X is upregulated and contributing to CVS significantly after SAH. Accordingly, this pending project is aiming to investigate this hypothesis though well-organized experiments, including molecular biological and cytological studies, gating properties research of ion channels, vascular contractility and hemodynamics studies in vivo and in vitro. This research group, including several dedicated cerebrovascular scientists, has extensive experience and ability to complete this project. The devices, equipments and other experimental necessities for the entire project are already definitely available. Taken together, we are dedicated to obtaining more evidence to consolidate the myogenic signaling concept in CVS pathogenesis, and, additionally, make a remarkable progress and provide a novel target for CVS research and intervention through studying myogenic ATP-P2X following SAH.