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动脉粥样硬化(atherosclerosis,AS)是由内皮功能障碍、脂质代谢紊乱、炎症细胞浸润等因素相互作用所致的以粥样斑块和纤维斑块为特征的血管系统慢性炎症。经皮冠状动脉介入治疗 (percutaneous coronary intervention,PCI)后再狭窄是由于球囊或支架治疗后内皮损伤,凝血系统激活和炎症反应导致各种细胞因子及生长因子的释放,最终导致管腔狭窄和管壁结构变化。尽管两种疾病的病因不完全相同,但是内膜损伤、炎症反应、平滑肌细胞增殖和细胞外基质沉积是它们共同的病理改变,在动脉粥样硬化或PCI后再狭窄发生和发展中起着关键作用,而血管外膜被认为只起支持和营养的作用,其作用长期被忽视。血管外膜由成纤维细胞、血管和淋巴管、神经末梢、祖细胞和免疫细胞等组成,使其成为血管壁结构中最复杂的一层[1-2]。成纤维细胞是血管外膜主要细胞成分,在多种因素的刺激下能活化为肌成纤维细胞(myofibroblast,MF),并增殖、迁移到新生内膜,分泌细胞外基质及炎症因子[3],参与体内多种病理过程的调节,促进AS和PCI后再狭窄的形成[4-5]。
动脉粥样硬化病变可能始于外膜,外膜成纤维细胞(AF)活化可能是AS的始发因素。Ogeng’o等[6]通过对108名平均年龄为34.6岁的肯尼亚黑种人进行尸检发现,14.8%的左前降支和11.1%的颈动脉外膜出现了增厚,其中,有6.5%的左前降支和3.7%的外膜增厚不伴随内膜增生,提示外膜的病变发生在中膜和内膜受损之前。在颈动脉外膜剥离的兔模型中,术后7 d发现手术组的血管损伤部位内膜增厚,并在14 d达到高峰。后期随着时间推移,内膜的损伤逐渐消退,但在42 d时对比假手术组仍存在差异,提示外膜损伤可导致血管内膜增生[7]。球囊损伤血管内膜后,外膜的炎症反应早于内膜且程度重于内膜[8]。研究发现,球囊损伤血管内膜后,外膜首先增殖,在术后7 d,外膜增厚最为明显,而内膜只有少量增生[9]。高脂喂养载脂蛋白E敲除(ApoE)(-/-)小鼠,处死动物前24 h腹腔注射5-溴脱氧尿嘧啶核苷(BrdU),不同时间分别取材。2周后,首先在主动脉外膜发现BrdU标记的阳性细胞,而内膜无变化;4周后发现外膜阳性细胞增多,内膜出现泡沫细胞,同时在损伤内膜也出现BrdU标记细胞;10周后,外膜BrdU阳性细胞并未发现明显增多,而内膜病灶进一步发展,可见纤维斑块,在损伤内膜出现更多的BrdU标记细胞。这些结果提示,在ApoE(-/-)小鼠动脉粥样硬化病灶形成过程中血管外膜成纤维细胞先于内膜出现增殖活性的变化,AF增殖与早期动脉粥样硬化病灶形成关系密切[10]。由此可见,无论是AS还是PCI后再狭窄,外膜首先发生增殖/增厚或发生炎症反应,这些疾病的发生可能是“由外向内”的病理过程[11-12]。
2.1 活化 当成纤维细胞受到损伤、缺氧、炎症、机械扩张等刺激时,在生长因子和细胞因子等的作用下,被激活并转化为肌成纤维细胞[2]。肌成纤维细胞兼有平滑肌细胞和成纤维样细胞特性,具有增殖、迁移和分泌的功能。MF最常见的标记物是α平滑肌肌动蛋白(α-SMA),由于正常平滑肌细胞和成纤维细胞来源的肌成纤维细胞均表达α-SMA,因此该蛋白不能区别这两种细胞,目前尚未发现肌成纤维细胞的特异性蛋白。
转化生长因子β(TGF-β)被认为是目前成纤维细胞表型转化的主要诱导因子。采用TGF-β1诱导体外培养的大鼠胸主动脉外膜成纤维细胞,发现RhoA-Rho激酶信号通路参与了TGF-β1诱导的血管外膜成纤维细胞向肌成纤维细胞的表型转化[13]。血管紧张素Ⅱ(AngⅡ)在外膜成纤维细胞的表型转化中也发挥着重要的作用[14]。He等[15]证明蛋白酶激活受体PAR1及PAR2细胞外信号调节激酶ERK1/2信号转导通路介导血管AngⅡ诱导的AF的表型转化、增殖与迁移。外膜成纤维细胞的不同亚群作用也不同,AngⅡ能诱导AF圆形细胞亚群更多地转化为肌成纤维细胞,推测圆形细胞亚群可能以增殖、迁移、分化为主,纺锤形细胞则主要负责自身组织的增殖等[16]。同时,AngⅡ也能促进成纤维细胞圆形亚群的迁移和上调内皮素前体原及I型胶原的表达,增加内皮素-1(ET-1)的分泌,通过产生趋化因子、细胞因子及活性氧簇(ROS)来调节血管的功能和结构[17]。骨桥蛋白(osteopontin)能够提高外膜成纤维细胞的增殖活性并促使其向肌成纤维细胞转化[18]。
2.2 迁移 外膜成纤维细胞活化后,α-SMA的表达上升,细胞迁移加快,AF迅速到达损伤部位,胶原在血管壁沉积。同时,AF在还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶(NADPH oxidase)作用下产生内源性活性氧,导致氧化型低密度脂蛋白的生成增加,从而进一步加剧动脉粥样硬化[19]。以往认为在血管损伤后,主要是中膜的平滑肌细胞进行增殖,致中膜增厚并迁移形成新生内膜。新的研究表明,将携带LacZ基因(编码β-半乳糖苷酶,β-gal)的腺病毒载体转染到血管外膜,发现动脉内膜损伤后,AF 由外膜迁移至中膜,最终到达内膜,参与新生内膜的形成;而只转染腺病毒没有损伤的血管,AF仍停留在外膜。这一基因工程的方法,为AF的迁移提供了直接证据[20]。AF的迁移过程是通过p27Kip1/CDK/pRb/E2F通路协同调节完成的[21]。肌成纤维细胞生成更多基质金属蛋白酶(MMPs),促进AF/MF穿过外膜到达中膜并迁移到内膜[18],促进PCI早期再狭窄的形成。
2.3 分泌 外膜成纤维细胞活化后分泌更多细胞外基质(extracellular matrix,ECM)和细胞因子促进AS和PCI后再狭窄的发生和发展。正常情况下,AF处于不分化的休眠状态,受到损伤或压力刺激时被活化为肌成纤维细胞,后者分泌更多的细胞外基质,特别是I型胶原增加,造成再狭窄血管内膜斑块局部体积的增加,加重了PCI后期管腔狭窄;外膜中I型胶原的增加使血管舒张受限,明显地降低血管的顺应性[9]。在ApoE(-/-)小鼠模型研究中,外膜成纤维细胞的增殖和迁移活性增强,能够分泌更多的TGF-β1、单核细胞趋化蛋白-1 (MCP-1)和胶原蛋白并参与动脉粥样硬化早期病灶的形成[22],TGF-β1可进一步诱导成纤维细胞的表型转化和细胞外基质沉积,MCP-1 可招募巨噬细胞、淋巴细胞等炎性细胞浸润,加剧炎性反应[8]。
3.1 AF参与一氧化氮(NO)的调节 正常情况下,内皮细胞分泌的一氧化氮是重要的内皮源性舒张因子,发挥舒张血管、降压、抗动脉粥样硬化的作用。NO是由L-精氨酸(L-Arg)和氧分子经一氧化氮合酶(NOS)催化合成的。NOS有三种亚型:诱导型一氧化氮合酶(iNOS)、神经元型一氧化氮合成酶(nNOS)、内皮型一氧化氮合酶(eNOS)。eNOS和nNOS催化产生的NO都能发挥抗AS的作用,前者能抑制血小板聚集、平滑肌细胞增殖与迁移、白细胞黏附及氧化应激反应[23],后者则通过扩张血管、抑制炎性分子聚集、防止血栓形成等产生作用。iNOS催化产生的NO通过与超氧阴离子结合生成过氧亚硝基阴离子[24],造成脂质过氧化和血管损伤,加速动脉粥样硬化形成。用原位杂交技术发现在一系列诱导因素的刺激下,血管外膜的NO信使核糖核酸表达和蛋白合成显著增加,产生大量NO,说明血管外膜是血管NO的主要来源之一[25]。研究发现血管外膜成纤维细胞具有独立的 iNOS/NO系统,参与血管功能的调节。脂多糖(LPS)能刺激外膜成纤维细胞表达iNOS,脂联素通过抑制AF上的AdipoR1-AMPK-iNOS通路,减少LPS诱导产生的NO,抑制AF向MF转化和增殖、抑制迁移到内膜从而减缓AS的形成[26]。另外用LPS处理单核巨噬细胞后,发现其可以通过白细胞介素-1(IL-1)激活外膜成纤维细胞的iNOS通路,激活的iNOS会增加蛋白的硝基化从而加剧胶原沉积和血管纤维化[27]。
3.2 AF参与氧化应激 吸烟、高血压、高血糖或血脂异常等导致内皮功能障碍,其致病的共同通路是刺激活性氧的产生和蓄积,发生氧化应激。血管损伤反应中,外膜成纤维细胞表达的NADPH氧化酶会产生大量ROS。Cascino 等[28]发现外膜成纤维细胞产生的过氧化氢(H2O2)不仅可以自分泌的方式作用于自身,还可以通过旁分泌的形式调节中膜的平滑肌细胞,促进血管收缩和血管重构。在ApoE(-/-)及p47phox双基因敲除的小鼠模型中,动脉粥样硬化损伤的程度较单纯ApoE(-/-)小鼠的轻,提示p47phox可能介导动脉粥样硬化的形成过程[29]。采用NADPH氧化酶抑制剂及敲除p47phox亚基,发现NADPH氧化酶活性及其产生的O2-下降,同时外膜成纤维细胞增殖和迁移受到抑制,提示AF可能通过p47phox这个靶点参与动脉粥样硬化形成的过程[30]。Liu等[31]发现同型半胱氨酸可通过上调大鼠外膜成纤维细胞Nox4,促进H2O2生成,从而介导外膜成纤维细胞表型转换,并分泌炎症因子,促进炎症细胞向外膜迁移。而过氧化氢酶是机体中重要的抗氧化酶,研究发现,血管紧张素Ⅱ诱导的AF会减少过氧化氢酶的表达和活性[32]。运用基因转染的方法,过表达过氧化氢酶可以降低α-SMA的表达,减少外膜成纤维细胞的表型转化、活性氧的产生以及胶原沉积从而减缓动脉粥样硬化的形成。这个作用可能是通过抑制AF上p38MAPK磷酸化产生的[33]。
3.3 AF参与免疫炎症反应 模式识别受体参与的外源性和内源性危险信号激活局部免疫反应的机制越来越明确,近期研究发现AF能够发挥免疫功能[34],其表达某些模式识别受体,例如Toll样受体(TLRs)[35]、NOD样受体(NLRs)[36]、晚期糖基化终末产物受体(RAGE)[37],活化的AF能作为固有免疫细胞识别外源性和内源性危险信号,通过产生大量的细胞因子和炎症因子,创造一个有利于巨噬细胞、树突状细胞激活和促进血液来源炎性单核细胞聚集的微环境,启动和传播外膜炎症[34,38]。在慢性炎症中,保持促炎性表型的AF能募集炎性单核细胞和树突状细胞前体[39-43],而AF表型持续性活化的分子机制仍是未知的,有研究推测可能是NF-κB信号通路在其中扮演了重要的作用。Wang等[44]证实LPS可以通过激活外膜成纤维细胞Toll样受体4(TLR4)下游的NF-κB信号通路上调人脂肪分化相关蛋白(ADRP)的表达及MCP-1的释放,促进脂质沉积,募集单核细胞并促进巨噬细胞泡沫化,加速动脉粥样硬化的形成。
血管炎症以往被认为是从内膜开始的,并通过中膜向外膜传播。近年来,大量研究证实血管外膜在心血管疾病过程首先被激活并且在启动血管炎症中发挥着重要作用。外膜炎症是AS的始发环节,是引起AS的始动因素[8,45]。
外膜成纤维细胞活化后能分泌大量的黏附分子、趋化因子、细胞因子。慢性缺氧环境下,AF分泌更多细胞间黏附分子-1(ICAM-1)和血管细胞黏附分子-1(VCAM-1),它们能促进AF迁移至内膜,使单核细胞、淋巴细胞趋化于血管内皮损伤处,顺着血管表面滚动、黏附至内膜[46]。高胆固醇血症刺激外膜成纤维细胞分泌MCP-1蛋白和mRNA表达[4],MCP-1能招募更多单核细胞,单核细胞随后分化成巨噬细胞,参与炎症反应,加速AS损伤的扩大[47]。促炎性因子肿瘤坏死因子α(TNF-α)、白介素6(IL-6)等可通过自分泌或旁分泌的形式参与炎症反应。
AngⅡ 能够上调血管外膜成纤维细胞中ICAM-1、P-选择素(P-selectin)、IL-6的表达,同时AF 对单核巨噬细胞的黏附、趋化作用增强,提示AF可能介导血管的炎症反应[48]。尾加素Ⅱ(UⅡ)能刺激血管外膜成纤维细胞分泌骨桥蛋白,促进TGF-β、IL-6、MCP-1的分泌,参与血管外膜的炎症反应过程和稳态的维持[49-51]。
Tieu等[4]研究证实,外膜成纤维细胞和巨噬细胞的相互作用在血管炎症的传播过程中发挥了重要作用。将人类急性单核细胞白血病细胞系(THP-1)和AF共培养后显示IL-6显著增多,AF还可促进单核细胞向巨噬细胞的转化,介导炎症反应。Li等[52]发现大鼠颈动脉球囊拉伤模型中,拉伤早期外膜就显著表达内皮转化生长因子(VEGF),向血管外膜注入抗Flt-1(VEGF的受体) 的多肽后外膜巨噬细胞浸润减少,新生内膜形成减少。体外实验中,VEGF 刺激的外膜成纤维细胞能增强巨噬细胞的趋化能力,介导血管炎症。用制瘤素和LPS协同作用于AF可以增加MCP-1、IL-6、VEGF表达,STATs、MAPK 激酶、NF-κB等信号通路被激活。结果提示制瘤素可以和Toll样受体4一起诱导AF促炎性反应,参与动脉粥样硬化[53]。
研究发现,内皮细胞可以抑制成纤维细胞活化。低氧环境中的成纤维细胞,当其和内皮细胞接触时,α-SMA的表达就会下降,说明成纤维细胞向肌成纤维细胞的表型转化减少,包括血管内皮生长因子A(VEGFA)、血小板衍化生长因子(PDGF)、纤维细胞生长因子(FGF)、基质金属蛋白酶2(MMP2)在内的促血管新生因子参与了上述过程[54]。在体外实验中证实内皮细胞能通过NO/cGMP通路抑制Ang Ⅱ诱导的AF表型转化,用高浓度的同型半胱氨酸(Hcy)处理内皮细胞后,Hcy削弱内皮型一氧化氮合酶的表达,内皮细胞抑制AF表型转化作用减弱,同时用L-Arg或cGMP类似物(8-Br-cGMP)培养的内皮细胞对AF的表型转化也产生了抑制作用,而使用eNOS抑制剂或鸟苷酸环化酶阻滞剂则会促进AF的表型转化[55]。
大量研究证实,血管外膜不再只是“旁观者”,而是作为重要的成员主动参与了AS和PCI后再狭窄的形成。当受到各种病理因素的刺激时,AF能发生表型转化为肌成纤维细胞,表达α-SMA,并迁移到中膜和内膜参与新生内膜的形成。活化后的AF可通过分泌黏附分子、炎性因子促进炎症反应,通过调节一氧化氮的合成和产生活性氧参与氧化应激从而促进AS和PCI后再狭窄的形成。关于AF与外膜其他成分,AF与内膜和中膜的关系有待进一步研究。希望通过对外膜的深入研究,寻找新的作用靶点,为预防AS及PCI后再狭窄的发生发展和早期干预提供新的思路和手段。
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