IKCa通道在周期性牵张调控血管平滑肌细胞表型转变、增殖、迁移中的作用及机制研究

Stretch influences the phenotype modulation, proliferation and migration of vascular smooth muscle cell (VSMC), further leads to some cardiovascular diseases, such as atherosclerosis and restenosis. Intermediate-conductance Ca2+-activated K+ (IKCa) channel mainly expresses in VSMC with synthetic phenotype, and its expression and activity are tightly related to the proliferation and migration of VSMC. It has been also demonstrated that the blockade of IKCa channel can decrease the development of atherosclerosis and restenosis. Furthermore, this channel is also stretch-sensitive. However, there is rare report on the relationship between the IKCa channel and VSMC function in response to stretch although they play some similar functions and shear some similar mechanisms as mentioned above. In view of this base, we rasie a scientific hypothesis "pathological stretch upregulates IKCa channel expression and promotes its activity, then actives the corresponding signal pathway, and further promotes VSMC phenotype modulation, proliferation and migration. Contrarily, phisological stretch behaves in a reverse way". To testfy this scientific hypothesis, the role and mechanism of IKCa channel in cyclic stretch-regulated phenotype modulation, proliferation and migration of VSMC will be explored in this project. This study aims to provide new insights into understanding the mechanism by which cyclic stretch influences the VSMC function and finding novel therapeutic strategy for cardiovascular disease.

牵张调控血管平滑肌细胞（VSMC）表型转变、增殖、迁移等功能，与动脉粥样硬化、血管成形术后再狭窄等疾病密切相关。中电导钙激活的钾通道（IKCa通道）主要表达于合成表型VSMC。研究证明，IKCa通道的表达和活性与VSMC的表型转变、增殖、迁移呈正相关。阻断该通道，可有效抑制动脉粥样硬化和血管成形术后再狭窄。尽管牵张和IKCa通道具有上述相似的功能，且IKCa通道为张力敏感通道，但目前对IKCa通道与牵张调控VSMC功能变化的关系没有任何报道。 鉴于此，本项目提出科学假设"病理性牵张通过上调IKCa通道表达、促进通道开放,进而激活相应的信号通路,促进VSMC表型转变、增殖和迁移。生理性牵张则相反"，并开展"IKCa通道在周期性牵张调控VSMC表型转变、增殖、迁移中的作用及机制研究"对上述假设进行验证，以期为深入理解周期性牵张调控VSMC功能变化的机制、找寻心血管疾病的治疗策略提供新依据。

背景：中电导钙激活的钾(Intermediate-conductance Ca2+- activated K+ channel, IKCa) 通道主要表达在合成表型的血管平滑肌细胞(Vascular smooth muscle cell, VSMC)上，与VSMC的增殖、迁移呈正相关。此外，IKCa通道也是力敏感通道，脐静脉内皮细胞的IKCa通道可被切应力激活。但目前对IKCa通道在周期性牵张调控VSMC功能变化中的作用尚无报道。.研究内容：本项目主要研究了IKCa通道在周期性牵张调控大鼠胸主动脉平滑肌细胞增殖、迁移中的作用及可能的机制。牵张条件包括：对照组（静态培养）、生理组（频率为1Hz、张应变为5%）、病理组（频率为1Hz、张应变为15%）。具体研究内容包括：1）不同牵张条件下IKCa通道基因及蛋白的表达变化；2）不同牵张条件下IKCa通道活性的变化；3）不同牵张条件下VSMC增殖的变化及IKCa通道阻断和Knock down后对其的影响， 4）不同牵张条件下VSMC迁移的变化及IKCa通道阻断和Knock down后对其的影响；5）不同牵张条件对VSMC胞内钙浓度变化的影响及IKCa通道阻断后的效果。6）不同牵张对VSMC p-ERK表达的影响。.重要结果：与对照组及生理性牵张相比，1）病理性牵张显著上调IKCa通道基因及蛋白表达、并增强其活性；2）病理性牵张促进VSMC的增殖和迁移。IKCa通道阻断和Knock down后，病理性牵张对VSMC增殖和迁移的促进作用得到明显抑制；3）生理和病理性牵张均促使VSMC胞内钙浓度升高，IKCa通道阻断可抑制病理性牵张所致的胞内钙浓度升高。3）病理性牵张促进p-ERK的表达。.结论和意义：IKCa通道参与了病理性牵张对VSMC增殖、迁移的促进，其机制与其介导的胞内钙浓度升高、激活ERK信号通路有关。该研究对理解病理性牵张所致血管疾病的发生发展提供了新的机制，同时也提示IKCa通道可能是治疗相关疾病的潜在药物靶标。.受本项目基金资助，完成SCI论文5篇，会议论文2篇，中文核心期刊论文1篇。培养硕士研究生6名。