心血管疾病(cardio vascular disease，CVD)的高患病率和高死亡率，使它成为威胁人类健康的头号杀手。探讨心血管疾病的发病机理，研究行之有效的心血管疾病防治策略是全世界研究者共同关注的热点。运动能明显改善心血管功能[1, 2] [3]，在CVD的初级和二级预防中，其作用发挥与药物干预措施相当[4, 5]甚至可能超过降压药[6]或降脂药物[5, 7]，有效降低CVD的发病率和死亡率。大多研究认为，其机制主要是运动通过改善心血管的“次级”风险因素(如血压、血脂、胰岛素抵抗、吸烟和肥胖等)，而最近有多项研究表明从心血管的“次级”风险因素的角度仅能部分解释运动对心血管保护的益处[8-11]。血管内皮功能障碍和血流动力学异常是心血管疾病发生发展的共同特征和关键事件[12]。运动会导致心脏和活动性骨骼肌血流量的大幅增加[13]，血管内皮细胞反复暴露于血流动力学刺激(如流体剪切力和跨壁压)中，引起血管功能和结构产生适应性变化[14]，改善血管内皮功能[15-18]。因此，有研究者认为运动诱发的血流动力学变化才是运动改善心血管功能的核心机制[19, 20]，而在运动引起血流动力学变化指标中，流体剪切力发生了急剧变化，触发各种血管内皮感受器，对分子信号进行感知和响应以保持心血管系统的稳态[21]。基于此本文将对运动介导血管内皮功能改善的流体剪切力响应的可能机制进行综述。

表2总结的是国家合作网络分析结果，显示美国很早就已经成为名物化研究的重要阵地，发文量比其他国家多几倍，而中国首次在国外核心发文时间为2013年，短短五年就累计发文14篇，排名第3。这说明中国也正逐渐成为国际名物化研究的前沿阵地。

1 流体剪切力是运动介导血管内皮功能改善的关键因素

1.1 运动与流体剪切力概述

血液是一种黏性液体，顺着流动的方向作用于血管腔侧壁单位面积上的力量称为流体剪切力，是血管直径和血管重塑的主要决定因素[22, 23]。流体剪切力作为力信号传导的重要刺激因素，作用于内皮细胞促发力学传导感受器，如酪氨酸激酶蛋白受体、G蛋白耦联受体、胞膜窖、细胞间连接复合物、整合素和基底黏着复合物和糖萼[24, 25]等，引起细胞沿流体方向的拉长和线性排列[26]，增强或抑制血管动态平衡中流体相关分子的基因表达[27, 28]。运动对流体剪切力的影响主要包括两方面，一方面是运动对流体剪切力大小的影响。随着运动强度的增加，人腹主动脉的流体剪切力可以从1.4～2 dyn/cm2增加至7～16 dyn/cm2，人股动脉流体剪切力可以从18dyn/cm2增加至60 dyn/cm2, 正如流体剪切力的计算公式所述，FSS表示流体剪切力，η表示粘度，Ri表示动脉内径，Q表示流量，运动期间Q增加，导致内皮细胞FSS增加，引起内皮细胞功能改变和表型适应[29-31]。另一方面，运动可以通过改变单向流和/或振荡流(顺向和逆向流)的频率和脉动幅度来影响流体剪切力。在人主动脉和腹主动脉上、下腹腔，运动可减少逆向血流流动从而降低振荡剪切力[32, 33]。在有氧运动(如单车运动)的初始阶段，肱动脉血流变得更振荡，即出现顺行和逆行两种方向的血流[34, 35]，其中血流逆行模式的增加是由于外周动脉阻力的增加[36]。随着运动的持续，动脉血流转变为顺行剪切力模式，发生与血管相适应的有利变化[37]。

2.5 评判指标 每一季度末将患者满意度(包括服务态度、巡视病房、打针技术、呼叫应答);患者对健康教育内容的知晓情况(包括病情、用药指导、康复指导);护士业务能力(包括理论考核及操作考核)的数据进行分析。

1.2 运动通过流体剪切力介导血管内皮功能改善

血管内皮是具有自分泌和旁分泌功能的重要器官，能感受血流动力学信号，具有调节血管通透性、血管紧张度、平滑肌细胞的生长和迁移、炎性反应和血小板功能的作用，对维持脉管系统的生理平衡至关重要[38]。血管内皮在响应各种不同危险因素过程中结构和功能的完整性受到破坏则会发生内皮功能障碍，这是心血管疾病发生的早期关键事件[12]。几十年来的研究已经表明运动可以改善血管内皮功能，甚至在改善青少年2型糖尿病的内皮功能和微血管功能方面独立于胰岛素敏感性的变化，并且停止运动后这种改善会被逆转[39]。虽然目前机制依然说法不一，但有体内和体外互补研究，直接和间接证据表明，流体剪切力是运动介导内皮血管功能改善的重要因素之一。

研究发现血管内皮功能障碍者的血液循环中的EPCs数量往往会发生减少和/或功能受损[100-103]，表明循环EPCs可提供内源性修复机制，以抵抗经风险因子诱导的内皮损伤并替代功能失调的内皮，对于维持内皮细胞健康起着重要作用[104-106] 。EPCs分为两类[107]：未 成熟的EPCs被定义为形成EPCs集落的循环血细胞(简称循环表型EPCs)，这些EPCs集落衍生自造血干细胞，并表达表面抗原如CD34、CD133，血管内皮生长因子受体2(VEGFR-2)、蛋白受体酪氨酸激酶和c-Kit，具有上皮特异性；随着差异转化过程，EPCs集落失去不成熟的标记，获得内皮或单核细胞标志物，如血管内皮钙黏蛋白(VE-cadherin)，E-选择蛋白(E-selectin)，整合素v/3(integrin v/ 3)和CD14，变成了第二类EPCs(简称组织表型EPCs)。从EPCs集落阶段到EPCs非集落阶段，是通过EPCs不间断地从悬浮方式循环表型转化为附着方式组织表型的过程，而这个过程往往发生在缺血或再生器官归巢后[108]。越来越多的证据表明，流体剪切力介导血管内皮功能改善，至少部分地与流体剪切力介导EPCs功能上调有关，同时流体剪切力还可以影响EPCs表型分化[109-111]。另外许多研究表明，运动可以增强EPCs的功能和进入血液循环的数量，提高流体剪切力则可增加循环表型EPCs迁移能力，改善EPCs功能，有利于细胞迁移到缺血组织以刺激血管生长[112-120] [121]，少数研究表明EPCs没有变化[122, 123]或者有所减少[124]。还有一些研究则发现EPCs循环数目没有变化，但运动确实能提高体外单位内皮集落[125]的形成和NO的产生[126]，其机制可能与CXCR4有关。

血管舒张和收缩分子之间的不平衡是发生内皮功能障碍的主要作用机制之一。运动训练可以引起内皮源性血管活性物质的变化，与运动方式和运动强度有关，长期有氧运动训练可以增加血管扩张剂如NO[49, 50]和前列环素(PGI2)[51, 52]等和减少血管收缩剂如内皮素-1(ET-1)[53, 54]等，虽然引起这些变化的机制尚无定论，但研究表明，运动介导血管活性物质平衡的机制至少部分取决于流体剪切力的变化。

研究表明，HUVECs用平行平板流动腔加载高水平层流流体剪切力24 h Nox2和Nox4 miRNA的表达降低[70]，Nox亚基gp91phox和p47phox miRNA的表达则随流体剪切力增大而下降[68]。当血管内皮细胞暴露于中高层流流体剪切力时，三种SOD亚型的表达(即CuZnSOD、MnSOD和ecSOD)均发生上调[71-74]。也有研究发现加载30 dyn/cm2层流流体剪切力20 h，MnSOD表达增加，但并未改变CuZnSOD蛋白的表达，可能是因为CAD的内皮细胞线粒体累积损伤，存在于线粒体内的MnSOD受剪切力的影响更为明显[68]。使用GPX同工酶GPX1缺陷型和GPX1过表达转基因小鼠的动脉实验表明，GPX与血管紧张素II诱导的内皮功能障碍发生发展有关[75]。加载5～20 dyn/cm2大小的流体剪切力4～24 h GPX miRNA表达呈时间和量级依赖的方式上调，同时GPX活性也增加[76]。

运动提高流体剪切力主要通过转录后和翻译后两种机制增加eNOS表达和活性，提高NO生成[49, 50]。eNOS基因启动子含有流体剪切应答响应元件，可以增加eNOS的活化[55-57]。eNOS蛋白具有多个丝氨酸/苏氨酸磷酸化残基，不同位点eNOS的磷酸化在调控酶活性中起重要作用，其中与运动相关的流体剪切力敏感的磷酸化位点是丝氨酸Ser-1177 [58]。经过4周的运动训练，CAD患者乳腺动脉的eNOS表达增加了2倍，Ser-1177磷酸化水平升高[59]，提示运动通过提高流体剪切力激活Ser-1177磷酸化，增加eNOS的活化。

2 运动介导血管内皮功能改善的流体剪切力依赖性可能机制

2.1 运动介导血管活性物质平衡的流体剪切力依赖性机制

直接证据：通过对无心血管疾病的健康男性实施多种运动策略，一方面通过无介入性监测手段分析流体剪切力的变化，另一方面则通过直接控制流体剪切力的大小(即手臂加热增加流体剪切力，捆绑袖带降低流体剪切力)分析血管内皮功能的变化。30min急性运动结果显示，与静息水平比较，握力、单车和加热条件下的无袖带组上臂流体剪切力和血流介导性扩张(flow mediated dilation， FMD)均有显著升高，而有袖带组上臂的流体剪切力和FMD均无显著变化[40]。8周运动训练结果显示，无袖带组手臂的肱动脉血管扩张的结构和功能均发生了时间依赖性适应性变化，而在有袖带手臂中则没有[41]。直接验证了流体剪切力是运动介导发生血管内皮功能改善和适应的生理学因素。

那几个人互相看了看，看起来他们对二十个警察还是心存忌惮的。愣了几秒钟，有个人挥挥手说，走。说着那人随手在院子里拎了一个喷雾气筒背在身上。以前就听说过，窃贼进家不空手，空手不吉利，这是行规。几个人走过我身边时，我看见其中一个人手里扬起了什么，等我意识到躲的时候已经晚了，我头上挨了一家伙，眼前一黑栽倒在地。倒地的同时，我听到了马兰尖厉的哭喊。

生态移民问题几乎在世界上任何一个国家都存在，如何实现“移得出、稳得住、有发展、能致富”是全世界共同的课题。

2.2 运动介导血管内皮氧化应激和炎症共重叠信号的流体剪切力依赖性机制

活性氧(ROS)产生与消除的失衡和慢性低水平全身炎症反应，会导致血管内皮功能障碍引发高血压，导致动脉粥样硬化等心血管疾病[60, 61]。ROS是氧化应激与炎症共重叠的信号通路中的中间环节，即可引发炎症，同时也是炎症过程的产物[62]。急性运动会增加氧化应激反应，也会导致骨骼肌收缩的短暂损伤，引起炎症反应[63]，增加血液中促炎细胞因子和急性期反应物[64]。而规律运动可以抵消和中和与心血管疾病相关的炎症与氧化应激恶性循环。

线粒体是多功能细胞器。它们不仅是代谢枢纽，而且还涉及其他重要的细胞过程。研究表明，线粒体对维持各种内皮稳态如ROS信号、Ca2+调节、凋亡和细胞衰老至关重要[90-92]。此外，线粒体功能障碍也与内皮功能障碍密切相关，是高血压和动脉粥样硬化等心血管疾病关键致病因素之一[90, 93, 94]。 因此，增强线粒体结构和功能的完整性是治疗内皮功能障碍的一种新的治疗选择。最近，许多研究表明[95-98]，血管内皮细胞中流体剪切力和线粒体生物发生之间存在潜在联系。运动可以提高层流剪切力水平，以血管内皮NO依赖的方式，显著改变了大鼠主动脉线粒体动态蛋白质谱[96]，上调PGC-1α和SIRT1增加线粒体生物发生[95]。有体外和体内互补研究，探讨流体剪切力对血管内皮细胞线粒体的生物合成和线粒体呼吸功能的影响。体外实验采用锥板流动腔装置模拟运动时的剪切力水平(15～30 dyn/cm2)，对人主动脉或脐静脉来源的内皮细胞持续加载20 dyn/cm2大小的流体剪切力24 h和48 h，间歇性加载72 h后，线粒体合成，线粒体质量控制，线粒体DNA含量和数量以及相关基因的表达显著增加，线粒体呼吸功能显著增强，线粒体膜电位(△ψm)降低。体内实验对小鼠进行5周自愿跑轮运动，由于血流再分配不同，剪切力变化不同，血流量和流体剪切力增加显著的大、小主动脉弓，胸主动脉弯曲和股动脉的线粒体含量显著增高。但是，血流分配相对较少、剪切力相对较低的肠系膜动脉上却观察不到这种变化[99]。

间接证据：内皮细胞暴露在大于10 dyn/cm2大小的单向层流流体剪切力呈现出抗动脉粥样硬化和血管保护性的表型，暴露在扰乱振荡流(即顺向流与逆向流同时存在)或小于4 dyn/cm2大小单向层流的流体剪切力容易激活致动脉粥样硬化表型[42] 。另有研究表明，逆行流体剪切力的增加会造成内皮功能的急性损害[43, 44]，顺行剪切力的增加则与FMD增强有关[40]。如前文运动与剪切力的关系所述，运动不仅能显著提高体内主要动脉流体剪切力大小，长期运动还能显著增加顺行剪切模式，从而改善血管内皮功能。Dick H. J.等人[35]对12名健康年轻男性进行不同类型和不同强度的下肢运动，用非侵入性实验手段高分辨率动脉超声和多普勒超声对上肢肱动脉顺行/逆行血流量和剪切速率进行分析发现[35]，与单车运动和直立行走两种运动相比，坐位双侧伸膝的心率增加并不明显，但其平均血流量和流体剪切力的增加最为明显，说明不能单从运动强度而忽略流体剪切力来衡量运动对心血管的影响。也有文献报道称运动训练后动脉中的内皮型一氧化氮合成酶(eNOS)表达并没有增加，即运动训练并没有改善血管内皮功能[45-48]。可能原因如前部公式所示，运动期间流量增加的同时动脉内径也发生适应性扩张，流体剪切力则可能没有发生变化，因此，不能引起血管内皮功能的改善，这也就从另一角度证明流体剪切力的改变可能才是运动改善内皮细胞功能的关键因素。

另一方面，规律运动通过增加血管内皮细胞的流体剪切力，降低了主动脉中NF-κB的活化[77]，调节炎症过程中的关键参与者NF-κB和MAPK信号调控SOD的基因表达和活性[78, 79]，高生理水平的层流流体剪切力也可以促发血管内皮细胞的抗炎模式，降低炎症标志物如C-反应蛋白(CRP)、TNF-α和IL-6[80-83]、VCAM-1和ICAM-1表达[84] [85]。与运动抗炎结果一致，体外对HUVECs加载12 dyn/cm2大小的剪切力进行预处理，然后用TNF-α和IL-1促发炎症，与对照组相比，预剪切组可以降低JNKs信号通路的活化，调节细胞凋亡[86] [87]。用脂多糖诱导HUVECS发生炎症反应和细胞凋亡，然后施加低(4 dyn/cm2)和高(15 dyn/cm2)大小的流体剪切力24 h, 高流体剪切力能更有效地抑制IL-6的产生[88]，也可诱导相关的TNFR-1与TNFR-2发生减少[89] 。

2.3 运动介导血管内皮细胞线粒体生物合成的剪切力依赖性机制

一方面规律运动可以减轻血液[65, 66]和心脏[67]中的氧化应激，激活高生理水平流体剪切力信号级联上调抗氧化防御机制，提高抗氧化系统的能力，降低氧化酶类的活性，从而改善内皮细胞的健康[68，69]。 其中血管内皮细胞内最主要的流体剪切力敏感氧化酶为烟酰胺腺嘌呤二核苷酸磷氧化酶(Nox)，流体剪切力敏感抗氧化酶为超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GPX)。

2.4 运动介导血管内皮祖细胞改善的流体剪切力依赖性机制

由两名研究者按照纳入与排除标准独立阅读文献标题与摘要，对文献进行初筛，符合标准的文献进一步阅读全文后进行复筛，并对最终纳入的文献进行资料提取，如有分歧由第三位研究者裁决或集体讨论解决。提取资料包括第一作者、发表年份、例数、年龄、疗程、干预措施、结局指标等。

CXC趋化因子受体4(CXCR4)是有7个跨膜域的G蛋白偶联受体，与配体趋化因子基质细胞衍生因子1(SDF-1)结合激活Janus激酶2(JAK-2)磷酸化[127]。CXCR4对于EPCs归巢到局部血管床以介导血管再内皮化至关重要，受损的CXCR4信号传导可能导致EPCs内皮修复能力的下降[128]。分离老年男性长期有氧运动训练前后的“早期”EPCs， CXCR4蛋白表达和JAK-2磷酸化水平显著升高，表明运动能提高与年龄相关的EPCs内皮修复能力[127]。而在体外用15 dyn/cm2流体剪切力预处理12 h的EPCs，对手术颈动脉剥离术后的老年裸鼠进行静脉注射，结果显示，EPCs的表达和EPCs的再内皮化能力增强。提示流体剪切力与天然配体SDF-1一样具有激活CXCR4 / JAK-2分子信号通路，增强EPCs内源性内皮修复能力的作用，是促进EPC功能的有效治疗策略。运动还可以诱导血液循环皮质醇增加，使T淋巴细胞中CXCR4的表达增加，从而影响EPCs细胞表面受体的表达及其作用。

2.5 运动介导microRNA(miRNA)改变的流体剪切力依赖性机制

研究表明，miRNA几乎影响动脉粥样硬化斑块起始、发生和进展的各个方面，包括炎症/趋化因子、胆固醇体内平衡、细胞黏附、血管细胞增殖/凋亡和EPCs功能。三类与运动相关受流体剪切力调控的内皮细胞表达的“机械敏感- miRNA” ：(1)抗动脉粥样化的机械性miRs，包括miR-143/145和miR-23b；(2)致动脉粥样硬化的机械性miRs，包括miR-221/222；(3)双重作用的机械性miRs，包括miR-21和miR-126。

有研究表明，VO2MAX65%运动1 h后循环miR-143/145上调。受流体剪切力影响的关键调节因子KLF2通过与miR-143/145的启动子结合正向调节miR-143/145在胞外囊泡的富集，使其从血管内皮细胞向SMCs转移，这种囊泡介导的miR-143/145的递送可以预防SMC去分化具有抗动脉粥样硬化作用。miR-221/222下调Dicer沉默引起的eNOS表达增加。Shlomit Radom-Aizik等人研究表明，年轻健康男性(20～30岁)进行10次2 min的循环蹬车测力器急性运动(相当于82%VO2MAX)，结果显示 19个miRNA的表达改变显著，其中包括机械敏感的miR-221显著下调。

在不同细胞类型和环境下，双重作用的机械性miRs的抗和致动脉粥样硬化反应不同。原因可能是单个miRNA可以靶向多个miRNA正向和负向调节基因反应。运动诱导血管内皮细胞释放miRNA进入血液循环，是运动适应的关键方面，miRNA-21是调节炎症、心肌功能、缺血缺氧性适应以及eNOS活性的重要miRNA。力竭运动后，miRNA-21上调了1.89倍，休息1 h后显著下调；持续运动90天后，受试者静息水平miRNA-21提高了2.63倍，但力竭运动后却并没有变化。表明miRNA-21受大强度急性运动调控，可能与它对炎症敏感性相关，长时间持续运动使其“变钝”，机体更能耐受力竭运动对机体炎性环境的改变其双重机械性和在运动中的变化，可能涉及miRNA-21调节作用的平衡机制。 miR-126在内皮细胞中高表达，不仅能调节血管内皮完整性和血管生成，还能影响炎性反应。不同运动强度运动方式下，循环miR-126浓度变化不同。如踏车运动4 h(VO2MAX为60%左右)，呼吸测功仪运动5 min(VO2MAX为40%左右)和马拉松运动，循环miR-126分别显著增加了4倍、2倍和3.4倍，但力量训练并没有影响其浓度，表明有氧运动比阻力训练更容易影响内皮功能。因此，研究不同类型运动对miRNA这个潜在治疗靶点的作用，提高“抗动脉粥样硬化”miRNA 或消耗“致动脉粥样化”miRNA，可以阻止或延缓内皮功能障碍的发生，降低心血管疾病的发生率。

3 总结

运动过程中流体剪切力是改善和血管重塑适应的主要生理刺激，其大小和模式的变化是保持血管内皮结构和功能完整性、维护心血管健康的关键，也是治疗心血管疾病的重要靶点。本文综述了运动介导血管内皮功能改善的流体剪切力依赖性机制，为进一步研究不同运动类型的剪切模式提供可参考的理论依据，未来期望能为有心血管疾病不能接受高强度运动或者活动受限的病人，提供模拟运动场景流体剪切力增高的另一“锻炼”途径。

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