远隔缺血适应通过调控脑血管平滑肌细胞TGF-β1/MKP-1/p38 MAPK通路改善脑梗死后脑血流自动调节功能的机制研究

急性脑梗死患者存在脑血流自动调节功能（CA）受损，是预后不良的独立危险因素。我们前期研究证实远隔缺血适应（RIC）可提高健康人的CA、上调TGF-β1的表达水平；并且发现RIC可改善大脑中动脉栓塞（MCAO）小鼠的CA，机制可能与TGF-β1对脑血管平滑肌细胞舒缩功能的调控有关。结合前期基础及国内外文献，我们提出RIC通过提高脑组织中TGF-β1的表达水平，激活脑血管平滑肌细胞Smad/MKP-1信号通路，进而抑制p38 MAPK介导的血管收缩反应，发挥改善急性脑梗死后CA作用的假说。本研究将应用脑血管平滑肌细胞、离体脑动脉环、p38 MAPK基因平滑肌细胞条件性敲除小鼠等，借助免疫荧光、单分子免疫阵列等技术明确RIC对脑梗死后CA的改善作用及机制。同时通过临床研究证实RIC对急性脑梗死患者CA的改善作用，并明确相关通路蛋白与CA的关系，为今后开展RIC治疗急性脑梗死提供新的理论依据。

Impaired cerebral autoregulation (CA) is an independent risk factor of poor prognosis in acute cerebral infarction (ACI) patients. In our previous studies, we found that remote ischemic conditioning (RIC) can increase CA and TGF-β1 levels in healthy adults, in addition, RIC also has the trend of improving CA in middle cerebral artery occlusion (MCAO) mice, the mechanism may be related to the regulation of TGF-β1 on the vasomotor function of cerebrovascular smooth muscle cells. Therefore, we hypothesize that RIC could up-regulate TGF-β1 level in brain tissue, which is followed by the activation of Smad/MKP-1 pathway in cerebrovascular smooth muscle cells, and thereby inhibit the vasoconstrictor response mediated by p38 MAPK, and finally improve CA after ACI. In this study, by using techniques such as cimmunofluorescence staining, single molecule array and others, models such as cerebrovascular smooth muscle cells, isolated cerebral artery segments, smooth muscle p38 MAPK conditional knockout mice, etc., we aim to investigate the effects and mechanism of RIC in improving CA after ACI. We will also try to clarify the effects of RIC on the improvement of CA in ACI patients, and verify the relationship between related pathway proteins and CA. This study will provide new theoretical basis for the treatment of ACI with RIC.