有氧运动逆转原发性高血压脑动脉重构中的钙火花/STOCs耦联机制

Essential hypertension is a major risk factor for stroke. To explore the pathogenesis of stroke and to find the simple and effective prevention measures have attracted more and more attention in the world. Although substantial evidence shows that moderate exercise can decrease the blood pressure and contributes to the reduction in overall morbidity of stroke, the underlying mechanisms are far from clarified. Ca2+ sparks/STOCs coupling on the vascular smooth muscle cells (VSMC) plays an important role in the negative feedback regulation of arterial tone. Localized intracellular Ca2+ release events through ryanodine receptors (Ca2+ sparks) in the sarcoplasmic reticulum are tightly coupled to the activation of Ca2+-activated K+ channels to generate spontaneous transient outward currents (STOCs), which provides a hyperpolarizing influence that opposes vasoconstriction. It is demonstrated that the dysfunction of Ca2+ spark/STOC coupling is one of the main causes of the functional change of cerebral artery induced by hypertension. However, it is still not clear about the role and mechanism of Ca2+ sparks /STOCs coupling in the effect of exercise on the hypertension-induced cerebral artery remodeling. In the present study, the spontaneous hypertensive rats will be given aerobic exercise training with different intensity. By using multiple techniques, including laser scanning confocal microscopy and patch-clamp technique, cardiovascular function investigation, micromyography, channel and relative protein expression measurement, we try to investigate the reversal effect of aerobic exercise on the hypertension-induced cerebral artery remodeling, and try to explore the role and potential molecular basis of Ca2+ sparks/STOCs coupling in this effect. The information gained will help us to understand the cellular mechanisms underlying the exercise therapy on hypertension.

原发性高血压是脑卒中的重要危险因素，探讨高血压致脑卒中的发病机理和寻找简单有效的防治手段已成为国内外的研究热点。适度运动可有效降低血压和卒中罹患率，但其作用的细胞机理还远未明了。血管平滑肌钙火花/STOCs耦联是重要的血管张力负反馈调节机制，由内质网Ryanodine受体介导的钙释放(钙火花)，可激活膜大电导钙激活钾通道产生自发瞬时外向流(STOCs)，诱导膜超级化和血管舒张；此二者耦联异常则是高血压致脑动脉功能改变的重要原因。然而此耦联在运动对高血压脑血管重构干预中的作用及其机制目前仍不清楚。本课题拟选用自发性高血压大鼠，施以不同强度的有氧运动训练，采用激光扫描共聚焦和膜片钳技术，结合动态心血管功能、离体微动脉反应性、通道相关蛋白表达检测等，系统观察有氧运动对高血压脑动脉重构的逆转效应，着重探讨钙火花/STOCs耦联在其中的作用及其潜在分子机制，旨为高血压运动疗法的细胞机理提供实验依据。

原发性高血压是脑卒中的重要危险因素，探讨高血压致脑卒中的发病机理和寻找简单有效的防治手段已成为国内外的研究热点。适度运动可有效降低血压和卒中罹患率，但其作用的细胞机理还远未明了。血管平滑肌钙火花/STOCs 耦联是重要的血管张力负反馈调节机制，由内质网Ryanodine 受体介导的钙释放（钙火花），可激活膜大电导钙激活钾通道产生自发瞬时外向流（STOCs），诱导膜超级化和血管舒张；此二者耦联异常则是高血压致脑动脉功能改变的重要原因。然而此耦联在运动对高血压脑血管重构干预中的作用及其机制目前仍不清楚。本课题选用自发性高血压大鼠（SHR），施以不同强度的有氧运动训练，采用激光扫描共聚焦和膜片钳技术，结合动态心血管功能、离体微动脉反应性、通道相关蛋白表达检测等，系统观察了有氧运动对高血压脑动脉重构的逆转效应，着重探讨钙火花/STOCs耦联在其中的作用及其潜在分子机制。研究发现（1）SHR的脑动脉和肠系膜动脉均呈现收缩张力增高和舒张功能下降；VSMC膜离子通道出现重构，表现为大电导钙激活钾通道（BKCa）功能增强（β1-亚基上调为主）、电压依赖性钾通道（KV）功能下调和（L型钙通道）CaV1.2功能上调，代表内质网Ryanodine受体（RyR）钙释放通道和膜BKCa功能联系的钙火花-STOCs耦联增强，提示高血压BKCa功能的改变实际上是动脉对血管内压力持续升高的代偿机制，并非导致高血压的原因，而KV功能下调和CaV1.2功能上调才可能是真正导致高血压外周阻力增高的原因；（2）规律的有氧运动可有效降低SHR的血压，改善动脉舒缩功能，其重要机制是有氧运动可显著抑制上述高血压动脉平滑肌的电-机械重构，逆转RyR-BKCa耦联病理性代偿上调，恢复动脉正常功能；（3）运动对高血压动脉电-机械特性的调控与运动强度密切相关，中等强度可显著抑制高血压动脉平滑肌CaV1.2结构和功能上调，缓解动脉张力增高；而高强度反而加强其上调，对动脉张力增高起恶化作用，提示高血压运动方案的制定中以低中强度为宜。该研究为阐明运动调控高血压动脉功能的细胞学机制提供了丰富的实验依据，研究结果也对高血压患者合理运动方案的制定提供了重要的数据支撑，不仅具有重要的学术价值，也对运动实践具有潜在的指导意义。