张应变诱导Piezo2蛋白在静脉血管内膜增生中的作用  

Role of Stretch-Induced Piezo2 in Neointimal Hyperplasia of Veins

作　　者：李萌潇 姚庆苹[1] 苑影 齐颖新[1] LI Mengxiao;YAO Qingping;YUAN Ying;QI Yingxin(Institute of Mechanobiology and Medical Engineering,School of Life Sciences and Biotechnology,Shanghai Jiao Tong University,Shanghai 200240,China;Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200080,China)

机构地区：[1]上海交通大学生命科学技术学院,力学生物学研究所,上海200240 [2]上海交通大学医学院附属第一人民医院,上海200080

出　　处：《医用生物力学》2025年第2期396-403,共8页Journal of Medical Biomechanics

基　　金：国家自然科学基金项目(12032003)。

摘　　要：目的探讨静脉血管暴露于动脉力学环境后Piezo2在静脉血管平滑肌细胞(vascular smooth muscle cells,VSMCs)功能异常及新生内膜增厚中的作用,揭示其在冠状动脉旁路移植术(coronary artery bypass grafting,CABG)和自体动静脉内瘘(arteriovenous fistula,AVF)术后静脉再狭窄中的潜在价值。方法通过GEO2R与GO分析AVF、移植静脉与正常静脉转录组数据的差异表达基因;免疫荧光染色检测2例AVF临床样本中Piezo2的表达情况。在体外细胞实验中,使用FX-5000^(TM)周期性张应变加载系统,对静脉VSMCs施加1.25 Hz、15%幅度的周期性张应变模拟动脉条件,Western Blot检测Piezo2、VSMCs表型标志分子SM22及增殖相关分子PCNA表达变化;应用无Ca^(2+)培养基去除细胞外Ca^(2+),分析Ca^(2+)对张应变引起的相关分子变化的影响。结果转录组学数据分析显示,与正常静脉相比AVF和移植静脉中Piezo2表达均上调。AVF临床样本切片的免疫荧光染色结果显示,与正常静脉相比,AVF组织中Piezo2表达上调;并且在AVF的增生内膜组织中显示出更明显的Piezo2表达上调和SMA表达下调。细胞实验结果显示15%张应变上调Piezo2、PCNA表达,下调SM22表达,提示动脉条件张应变促使静脉VSMCs从收缩型向合成型表型转变;去除细胞外Ca^(2+)部分逆转了张应变引起静脉VSMCs表型转换与增殖。结论静脉暴露于动脉力学环境后,可能通过上调Piezo2诱导VSMCs表型转换促进静脉血管内膜增生。研究结果为CABG和AVF术后静脉再狭窄的防治提供基于力学生物学的新思路和潜在靶点。Objective To explore the role of Piezo2 in venous vascular smooth muscle cell(VSMC)dysfunction and neointimal hyperplasia following exposure of veins to an arterial mechanical environment,and elucidate its potential role in venous restenosis after coronary artery bypass grafting(CABG)and arteriovenous fistula(AVF)surgery.Methods Based on transcriptomic datasets,differentially expressed genes between AVF or grafted veins with normal veins were analyzed using GEO2R and GO.Immunofluorescence was used to detect expression of Piezo2 in two AVF clinical samples.The FX-5000^(TM) cyclic stretch application system was used to apply 1.25 Hz stretch with 15%amplitude to VSMCs to simulate arterial conditions in vitro.The protein expressions of Piezo2,SM22(VSMC phenotypic marker),and PCNA(proliferation-related molecule)were 396 measured with Western Blot.The calcium-free medium was further used to remove extracellular Ca^(2+),and the effect of Ca^(2+)on stretch-induced changes in related molecules were analyzed.Results Transcriptomic analysis revealed that Piezo2 was upregulated in AVF and grafted veins compared to normal veins.Immunofluorescence showed the increased protein expression of Piezo2 in AVF tissues compared to normal veins.Notably,in the neointimal tissue of AVF samples,Piezo2 was significantly upregulated,while SMA was downregulated.In vitro,15%cyclic stretch upregulated Piezo2 and PCNA expression but downregulated SM22 expression,which suggested a phenotypic switch of venous VSMCs from the contractile phenotype to the synthetic phenotype.Removal of extracellular Ca^(2+)partially reversed the stretch-induced VSMC phenotypic switch and proliferation.Conclusions After veins are exposed to an arterial mechanical environment,the upregulated Piezo2 may induce neointimal hyperplasia by promoting VSMC phenotypic switch.This study may provide mechanobiological insights and potential therapeutic targets for the prevention and treatment of venous restenosis following CABG and AVF surgeries.

关 键 词：Piezo2 静脉内膜增生 血管平滑肌细胞 张应变 

分 类 号：R318.01[医药卫生—生物医学工程]