Advances in Clinical Medicine
Vol.
13
No.
07
(
2023
), Article ID:
69707
,
10
pages
10.12677/ACM.2023.1371700
平滑肌细胞与腹主动脉瘤发病机制的研究概述
张霞,郭莹*,陈雪英
济宁医学院临床医学院,山东 济宁
收稿日期:2023年6月25日;录用日期:2023年7月19日;发布日期:2023年7月28日
摘要
腹主动脉瘤(AAA)是一种致命的血管退行性病变,其发病机制十分复杂,根据2022版腹主动脉瘤诊断治疗专家共识,AAA特征是腹主动脉的永久性局部扩张(气球样膨胀)超过正常直径50%以上,破裂和相关的灾难性生理损伤的总死亡率超过80%。病理特征是以中膜缺陷为主的主动脉壁结构破坏。AAA的发生涉及多种病理过程,包括细胞外基质降解、炎症、氧化应激、平滑肌衰老、凋亡及表型转化。目前关于AAA的治疗,手术仍是唯一的治疗手段,现仍未有高级别证据支持药物可以有效缓解甚至逆转AAA的发展,所以需要进一步了解AAA病理生理机制。平滑肌细胞(VSMC)是动脉壁中膜最主要的细胞类型,平滑肌细胞的衰老、凋亡、炎症反应以及与平滑肌细胞有关的细胞外基质的降解共同导致血管壁受损,促进AAA的形成。本文以平滑肌为中心,表述平滑肌与腹主动脉瘤之间的关系,这可能为AAA的治疗及预防提供新的思路。
关键词
腹主动脉瘤,平滑肌细胞,平滑肌表型转化
Overview of Studies on Smooth Muscle Cells and the Pathogenesis of Abdominal Aortic Aneurysms
Xia Zhang, Ying Guo*, Xueying Chen
School of Clinical Medicine, Jining Medical College, Jining Shandong
Received: Jun. 25th, 2023; accepted: Jul. 19th, 2023; published: Jul. 28th, 2023
ABSTRACT
Abdominal aortic aneurysm (AAA) is a fatal vascular degenerative diseases, its pathogenesis is complex, according to the 2022 edition of expert consensus, diagnosis and treatment for abdominal aortic aneurysm AAA is characterized by the permanent local expansion of abdominal aorta (ballooning inflation) than normal diameter by more than 50%, rupture and the associated total mortality of more than 80% of catastrophic physical damage. The pathological feature is the destruction of aortic wall structure mainly due to media defect. The occurrence of AAA involves various pathological processes, including extracellular matrix degradation, inflammation, oxidative stress, smooth muscle aging, apoptosis and phenotypic transformation. At present, surgery is still the only treatment for AAA, and there is still no high-level evidence to support that drugs can effectively alleviate or even reverse the development of AAA. Therefore, it is necessary to further understand the pathophysiology of AAA. Smooth muscle cells (VSMCS) are the most important cell type in the media of arterial wall. Aging, apoptosis, inflammation and degradation of extracellular matrix related to smooth muscle cells jointly lead to the damage of vascular wall and promote the formation of AAA. This paper focuses on smooth muscle and describes the relationship between smooth muscle and abdominal aortic aneurysm, which may provide new ideas for the treatment and prevention of AAA.
Keywords:Abdominal Aortic Aneurysms, Smooth Muscle Cells, Smooth Muscle Phenotype Transformation
Copyright © 2023 by author(s) and Hans Publishers Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
1. 引言
在过去的研究中,性别、年龄、吸烟、血脂水平等各种因素均与AAA的形成发展有关 [1] ,随着全球人口老龄化的发展,AAA的发病呈逐年上升的趋势,是造成65岁以上老年人死亡的主要原因 [2] 。根据各种筛查研究发现,AAA的患者男女比例在3.5~6.1之间,且常见于老年男性 [3] 。
AAA的病理学特征主要是炎症、ECM的降解、EC的功能障碍、VSMC的表型转化以及,导致局部永久不可逆扩张,最终破裂 [4] 。AAA的基本特征是主动脉壁的炎症伴随炎性细胞的浸润,在临床和实验性AAA中,均可见许多促炎因子的升高,如单核细胞趋化蛋白1 (MCP-1)、白细胞介素-1β (IL-1β)、IL-6和肿瘤坏死因子-α (TNF-α)。这些炎性介质与炎性细胞相互作用,促进了后续的炎症反应以及EC及VSMC功能障碍、ECM降解,最终导致AAA [5] 。VSMC是中膜最主要的细胞类型,现已有很多研究表明VSMC在AAA的形成发展中起到至关重要的作用。现尚无特效药物预防甚至逆转AAA进展。
2. 平滑肌细胞的凋亡
VSMC的凋亡被认为是AAA进展中的关键病理改变,主动脉壁VSMC数量的减少使得产生弹性蛋白、胶原蛋白等细胞外基质的能力下降,动脉管壁的韧性和强度减低,从而导致AAA的形成 [6] [7] 。细胞凋亡产生凋亡小体,凋亡小体若没有被及时清除,可以促进钙沉积在管壁,使血管硬化,从而促进AAA的进展 [8] 。导致VSMC的凋亡的因素很多,包括炎症因子、缺氧、PDGF等生长因子、缺氧以及DNA损伤等 [9] [10] 。另外,细胞的老化最终也会走向死亡,在死亡介导因子Fas/FasL信号被激活之后,激活caspase级联(Caspase-3和-7),诱导染色体DNA降解和细胞凋亡 [11] 。此前已有研究报道了在AAAs中Fas/FasL在VSMC中被激活 [12] 。现又越来越多的证据表明ER应激、氧化应激和弹性蛋白酶均可诱导VSMC凋亡,其中Serpin蛋白酶抑制剂B9 (SerpinB9)可以抑制弹性蛋白酶诱导的细胞凋亡 [13] 。自噬有关的凋亡也与AAA的发展密切相关,转录因子EB(TFEB)作为MITF/TFE家族的一个成员,作为自噬和溶酶体生物发生的主调控因子,在内皮细胞、巨噬细胞及平滑肌细胞中均有表达,其中在内皮细胞中TFEB具有减少动脉粥样硬化并促进缺血后血管形成的作用 [14] 。TFEB可以通过调节凋亡信号通路特别是上调BCL2来抑制VSMCs的凋亡,此研究还证明了2-羟丙基-β-环糊精(HPβCD),可以激活TFEB并通过VSMC依赖的方式抑制小鼠AAA的形成和发展 [15] ,在不同的AAA临床前模型中,VSMC特异性敲除TFEB增强VSMC凋亡并促进AAA形成 [15] 。自噬的关键调节因子ATG7的敲除也会加重血管紧张素II相关的主动脉重塑 [16] 。
越来越多的研究证明非编码RNA在调节VSMC的凋亡中的重要作用。许多研究报道,miR-21是几种心血管疾病中最常见和最显著的解除调控的miRNA [17] ,也是唯一被证明通过调节SMC增殖和凋亡在AAA形成中发挥核心作用的miRNA [18] 。miR-21的过度表达,可以使得磷酸酶和张力蛋白同源物(PTEN)表达降低,导致Akt磷酸化和活化,从而抑制VSMC凋亡 [18] 。有研究表明,在AAA组织中表达明显升高的长非编码RNA GAS5,直接靶点作用于Y-box-binding蛋白1 (YBX1),与GAS5形成正反馈环,调节下游靶点P21,抑制VSMC的增值并诱导其凋亡,从而促进AAA的形成。另有研究报道GAS5作为miR-21海绵释放PTEN,阻断Akt的活化和磷酸化,从而抑制SMCs增殖,促进凋亡。因此有研究提出,GAS5通过同时调节蛋白和miR-21来刺激SMC的凋亡和增殖,最终参与AAA的形成 [19] 。最近有研究证明,GAS5还可能通过与EZH2结合激活RIG-I信号通路,导致SMCs凋亡 [20] 。GAS5还可以通过激活血管重塑中的p53信号通路,抑制血管平滑肌细胞增殖,促进细胞凋亡 [21] 。另有miR-26a也可以通过抑制VSMC凋亡来抑制AAA的形成 [22] ,通过抗MIR转染抑制miR-26a促进H2O2诱导的人主动脉SMCs凋亡 [16] 。另有长链非编码RNA H19可以通过HIF-1α诱导平滑肌细胞凋亡,H19可以通过结合细胞质HIF-1α,HIF-1α直接与MDM2相互作用,阻止MDM2介导的p53 (主抑癌基因)降低,诱导SMC的凋亡 [23] 。最近有实验证明,针对长链非编码RNAH19干扰可以阻止AAA的进展,并且能抑制HIF1α信号及其在动脉瘤发展过程中对VSMCs的凋亡作用 [24] 。在Ang II诱导的小鼠AAA模型中,LncRNA pVT1的过度表达可诱导VSMC凋亡,使MMP-2和MMP-9升高,TIMP-1降低。相反,阻断PVT1在体外和体内均可以逆转这些作用 [25] 。以上发现均说明了非编码RNA在VSMCs凋亡中至关重要的作用。
赖氨酰羟化酶1 (LH1)的缺失可引起VSMC的凋亡。研究表明,LH1缺失引起的胶原蛋白交联受损可能引发异常的机械感知,从而引起血栓软骨素-1 (Thbs1编码)的表达上调,导致基质金属蛋白酶(MMP)活性增加以及VSMC大量凋亡 [26] 。其中,MMP不仅可以降解ECM,还可以调节VSMC的增殖、迁移和凋亡,但MMPs介导VSMC凋亡的直接证据仍有待于进一步研究 [6] 。
3. 平滑肌细胞与细胞外基质的降解
AAA的基本病理改变是细胞外基质(Extracellular matrix, ECM)过度降解和重塑,对主动脉的扩张甚至最终的破裂至关重要。弹性蛋白和胶原蛋白是主动脉血管壁ECM的主要成分,它们决定了管壁的弹性和韧性,共同维持主动脉机械强度,抵抗血管的扩张和破裂 [6] 。基质金属蛋白酶(MMPs)对血管胶原和弹性蛋白等细胞外基质的降解是AAA形成的关键 [27] 。平滑肌细胞(Smooth Muscle Cells, SMC)的是动脉管壁中膜中最主要的细胞类型,在健康的脉管系统中,ECM为管壁细胞提供稳固的物理支架,一方面,VSMC可以产生弹性蛋白和胶原蛋白修复ECM,另一方面,VSMC通过MMPs和组织金属蛋白酶抑制剂(TIMPs)的降解ECM,维持血管的稳态 [6] [7] 。
在AAA病变处,基质金属蛋白酶-2 (Matrix metalloproteinase-2, MMP-2)和基质金属蛋白酶-9 (Matrix metalloproteinase-9, MMP-9)在VSMC中显示出明显的上调 [28] ,MMPs抑制剂中TIMP-1和TIMP-2缺乏增加,提示一种不平衡的蛋白水解状态 [29] [30] 。传统认为,SMC主要表达MMP-2参与到ECM降解 [27] 。有研究报道,SMC特异性肝激酶B1 (LKB1)表达缺失会加剧血管紧张素II诱导小鼠的AAA形成,并伴有AAA发生率增加和主动脉扩张。LKB1是一种肿瘤抑制因子,是细胞极性和能量平衡的中枢调节因子。机制上,LKB1可与MMP-2转录因子特异性蛋白1 (SP1)结合,从而降低SP1与MMP-2启动子的结合,从而抑制MMP-2的表达,提示LKB1可能通过抑制MMP-2的表达在AAA的形成中起保护作用,可作为AAA疾病的潜在治疗靶点 [31] 。
有实验通过在标记的不溶性弹性蛋白和小鼠主动脉切片上孵育VSMC,证实AAA来源的VSMCs比非扩张的肾下主动脉或颈动脉斑块来源的细胞能够降解更多的不溶性弹性蛋白调,AAA中的VSMC可以通过MMP溶解弹性蛋白参与ECM的降解。实验表明,在激活的巨噬细胞环境中,动脉瘤来源的VSMC协同大量生产弹性蛋白酶,特别是MMP-9显著增加 [28] ,具体分子机制仍需进一步探究。巨噬细胞不仅可以与VSMC协同产生大量MMP9参与基质的降解,还可以表达netrin-1,它一方面可以诱导白细胞迁移,另一方面可以通过结合其受体neogenin-1诱导VSMCs内钙离子的内流,对基质金属蛋白酶-3 (MMP3)进行转录调控和持续催化活化,促进AAA中ECM的局灶性降解。此外,netrin-1还可以通过结合激活其受体neogenin-1,活化T细胞的转录因子核因子细胞质3(NFATC3)的核易位,从而增强基质金属蛋白酶3 (MMP3)的催化活性。在动脉瘤组织中,微钙化丰富的区域显示出广泛的弹性蛋白断裂,Netrin-1可能可以同步细胞内钙池,而钙池可能在广谱范围内协调VSMCs的功能 [32] 。钙是维持血管壁细胞稳态的关键辅助因子,钙库的异常调节现被认为是包括动脉粥样硬化和马凡综合征等动脉疾病的原因 [33] 。
4. 平滑肌细胞的表型转化
动脉壁分为内膜、中膜和外膜,腹主动脉属于弹性动脉,中层厚,VSMC及ECM是中膜最主要的组成部分。VSMC具有高度可塑性,可在两种表型之间发生转化,收缩表型和增殖/合成的表型。在健康的血管壁中,VSMC主要是以收缩型为主,通过其收缩和舒张维持血管张力 [34] [35] ,保持血压稳定。分化的VSMC呈纺锤形,表达高水平的收缩蛋白,如α-平滑肌肌动蛋白(α-SMA)、SM肌球蛋白重链(SMMHC)、平滑肌22α (SM22α)、SM-calponin (CNN)和smoothelin-B [36] 。在病理条件下,VSMCs可被转化生长因子-β (TGF-β)、PDGF-BB、Ang II等诱导,去分化转变为增殖/合成表型 [35] [37] [38] [39] 。VSMCs收缩功能的丧失可能降低血管张力,管壁从而促进动脉瘤的形成 [38] [40] 。一些早期的研究已经揭示,促进SMC分化能够抑制实验性AAA形成 [41] [42] 。在人AAA活检中,TGF-β受体2 (TGFBR2)显著下调 [43] ,最近有一项使用SMC特异性缺失TGFBR2的谱系追踪研究,在ApoE-/-背景下,那些SMC中缺乏TGF-β信号的小鼠在高胆固醇高脂肪饮食4个月后发生了AAAS,而野生型小鼠没有 [44] 。另有与TGF-β相互负调节彼此转录的VEPH1,一个与肝细胞肝癌发生发展相关的重要抑癌基因,在Ang II诱导的主动脉中膜中表达 [45] ,当在其过表达时能够加剧Ang II诱导AAA,并抑制重组TGF-β1诱导的MYH11和α-SMA的增加,抑制Smad3的磷酸化和核积累,促进SMCs的合成表型转换 [46] 。Veph1对SMCs中TGF-β/Smad3通路的负调控作用还得到了Shathasivam小组在癌细胞中报道的早期发现的支持 [47] [48] [49] 。以上充分说明TGF-β信号转导对维持SMCs的结构完整性和防止AAA时主动脉扩张是必要的。
小型非编码RNA microRNA (miRNA)也可以调控VSMC的表型转换,miRNA可以通过降解信使RNAs或模拟小干扰RNAs抑制基因翻译来抑制基因表达。有研究已证实,在细胞中存在一个21-nt具有高度序列保守性的microRNA——microRNA-126A-5P (miR-126A-5P),负责调节SMC功能。miR-126-5P的异位过表达可以恢复SMC的分化——收缩型/分化型SMC标志物平滑肌肌球蛋白重链(MYH11)和α-平滑肌肌动蛋白(α-SMA)的表达增加,而合成型/去分化型SMC标志物增殖细胞核抗原(PCNA)和波形蛋白的表达减少 [50] 。它还可以通过下调ADAM金属肽酶与血小板反应蛋白1型基序4 (ADAMTS-4)起到抗AAA的作用,ADAMTS-4是一种调节基质降解的分泌型蛋白酶 [51] ,作为血管平滑肌细胞分化的负调节因子,与miR-126-5P在小鼠腹主动脉中的表达呈负相关 [50] 。另有miR-143/145簇在血管平滑肌细胞中高表达,在心脏和主动脉中表达最为丰富,血清反应因子(SRF)、肌红蛋白和NKX2.5可诱导SMCs中miR-143/145的表达 [52] [53] 。miR-145的过度表达提高了SMC收缩蛋白的水平,包括α-SMA、SMMHC和CNN。 miR-145增强平滑肌细胞收缩能力的作用主要是通过抑制Kruppel样转录因子4 (KLF4)和KLF5抑制肌红蛋白下调VSMC分化标志基因 [53] 。
此外,有研究表明,FoxO3A通过P62/LC3BII自噬信号通路促进VSMC表型转换以加速AAA的形成 [54] 。在AAA中,维持VSMCs的收缩表型的PI3K/Akt信号通路 [55] [56] [57] ,可以通过抑制Foxo转录因子(尤其是FoxO3A和FoxO4) [57] [58] 活性,抑制AAA的形成;VEPH1对此通路亦有调控作用。最近的一项研究表明,XBP1U-FOXO4-Myocardin轴通过维持VSMCs的收缩表型,在预防主动脉瘤形成中起着关键作用,这进一步表明了FOXO转录因子在血管疾病中的新作用 [59] 。FOXO3A还在抑制VSMC增殖和促进VSMC凋亡方面发挥重要作用,表明FOXO3A可能在AAA从发病到整个疾病进展的发病机制中发挥核心作用 [54] 。先前的一项研究表明,抑制自噬可以阻止PDGF诱导的表型转换,表明自噬在VSMC表型转换中起重要作用。FoxO3A已被证明在各种细胞的自噬中起关键作用 [60] [61] [62] 。
在微环境改变的情况下,VSMCs部分由收缩型转化为其他表型,采用巨噬细胞样分泌杂交作用;也可以继承增强的收缩电位 [63] 。SMC表型与ECM组成和组织之间存在双向的关系,SMC表型改变可能影响ECM的降解和合成,这与SMC表达蛋白酶及其抑制剂的制衡有关,而ECM也被证明影响SMC表型和SMC对机械刺激的反应 [64] 。众所周知,当收缩刺激时,形成ECM粘附复合物的蛋白质在细胞膜上组装,并触发肌动蛋白丝的聚合,从而增强细胞膜 [65] ,这种现象在富含肌动蛋白的细胞中更加明显。这有助于将由细胞内肌球蛋白重链精心策划的收缩机制所产生的力传递给ECM,从而使细胞适应其环境中的机械应力 [66] 。在AAA微环境中的巨噬细胞也对SMC的表型产生影响,在AAA中VSMCs有一个独特的前弹性溶解表型,它可以通过MMP-9合成控制的转录后失败导致弹性溶解性MMP的产生和激活增加而发生的。在激活的巨噬细胞的环境下,这种表型会增强,但具体细胞内及细胞间的机制需要进一步研究 [28] 。
在血管壁中还存在一系列多能祖细胞,具有高度增殖及分化成包括平滑肌及内皮细胞等细胞后代的潜力。这些细胞可能从出生一直持续存在,并影响出生后的生长、衰老和疾病。谱系追踪研究表明,在病变血管壁中,SMC经历了多种表型转变,其特征在于表达替代细胞类型的标志物,并通过有限数量的内侧SMC的寡克隆扩增来填充受伤或患病的血管 [67] 。在血管壁中存在一种由骨髓间充质干细胞衍生的平滑肌细胞(BM-SMCs),它可以在PDGF (血小板衍生生长因子)和TGF-β1 (转化生长因子-β1)存在下在2D纤连蛋白底物上分化BM-MSCs产生一种更加稳定的BMSMC表型(cBM-SMC),其MYH11和α-SMA表达相对增加 [68] ,还分泌具有促弹性和抗蛋白酶水解的生物因子作用于血管的SMC [66] ,从而起到一定抵抗AAA形成发展的作用。在此理论研究基础上,可进一步探索是否可以通过细胞疗法达到延缓甚至逆转AAA发展的作用。另有研究发现,SMC的分化不仅可以在收缩表型(表达MYH11、ACTA2和TAGLN)和去分化的合成表型(表达COL1A1、MGP和COL3A1)之间转变 [69] ,还可以转化为其他类型的细胞,如软骨细胞样细胞(SOX9+、Runx2/Cbfa1+)、泡沫细胞和巨噬细胞样细胞(Oil Red O+、LGALS3+和Mac3+)、间充质干细胞样细胞(Sca1+)、肌成纤维细胞(PDGFβR+)或米色脂肪细胞样细胞(UCP1+) [67] 。
5. 平滑肌细胞的衰老
AAA的患病风险随着年龄而增加 [70] ,据资料查证动脉瘤的SMC是衰老的 [71] ,衰老的细胞通过分泌相关介质,典型的如IL-1、IL-6、IL-8和单核细胞趋化蛋白-1等 [72] ,这些因子可以通过旁分泌/自分泌机制诱导邻近细胞的衰老 [73] 。有研究发现,Myocardinrelated转录因子(MRTFs)家族成员之一,Myocardin相关转录因子A (MRTFA, MKL1)的缺乏能抑制血管衰老,并显著减少动脉瘤的发生率,减轻病理变化程度。相反,其活性增加是包括血管再狭窄、动脉粥样硬化及血管纤维化在内的多种血管并发症发生的基础 [74] 。MKL1已被证明在损伤性狭窄、动脉粥样硬化和缺氧性肺紧张等几种血管疾病中起着重要的作用。野生型与MKL1敲基因小鼠的对比,野生小鼠SA-β-gal活性增加,p16、p21和p53等衰老标志物表达增加,在细胞水平的实验中,MKL1缺乏在mRNA和蛋白水平上都减轻了Ang II诱导的一种明确的衰老标志物p16 (CDKN2A)的表达。并且还在VSMCs中找到了p38MAPK激活血管炎症和衰老的机制途径 [75] ,组成了关键的动脉瘤前通路。除文献记载的p38MAPK的促炎作用外,该途径已成为细胞衰老的一个关键激活因子,并有助于多种衰老相关疾病,如癌症和认知功能衰退 [76] [77] 。但p38MAPK调控血管炎症和衰老的详细分子机制仍有待进一步研究。
沉默信息调节因子1 (sirtuin1, SIRT1)是哺乳动物最具特征性的sirtuin,在血管中高表达,调节健康和疾病中心血管功能,SIRT1对应激诱导的血管重塑、腹主动脉瘤、主动脉夹层和小鼠动脉粥样硬化有保护作用,在ANG II以及氯化钙(CaCl2)诱导的AAA模型中均证明了SIRT1对AAA形成的抑制作用。DNA损伤驱动细胞老化 [78] ,细胞暂时退出细胞周期,进行DNA的修复,当损伤超过修复能力,发生细胞的衰老或凋亡。SIRT-1通过p53依赖的机制,可以促进DNA修复和调节细胞周期,从而促进活力和寿命 [79] 。从机制上看,SIRT1的减少可促进血管细胞衰老,上调p21的表达,增强血管炎症反应。此外,SIRT1对p21依赖性血管细胞衰老的抑制阻断了Ang II诱导的NF-κB与单核细胞趋化蛋白-1 (MCP-1/CCL2)启动子的结合,并抑制了其表达。总之,VSMCs中SIRT1的年龄相关减少通过促进p21依赖性血管细胞衰老、炎性细胞募集分子分泌和血管炎症而使主动脉易发生AAAS [80] 。另外众所周知在过敏性哮喘的气道炎症和重塑中起关键作用的IgE,可以通过激活lincRNAp21-p21途径诱导SMC衰老 [81] 从而促进AAA的形成。
6. 结语
AAA是致死率极高的心血管系统疾病,主要见于老年人,对公众的生命健康造成威胁。目前对于AAA的治疗除手术外仍没有有效的药物治疗。本文关于平滑肌细胞在AAA形成发展中的作用作一综述,然而还有许多机制仍未被探究,分子机制尚不明确,这需要我们对AAA的病理机制作进一步的了解。
文章引用
张 霞,郭 莹,陈雪英. 平滑肌细胞与腹主动脉瘤发病机制的研究概述
Overview of Studies on Smooth Muscle Cells and the Pathogenesis of Abdominal Aortic Aneurysms[J]. 临床医学进展, 2023, 13(07): 12126-12135. https://doi.org/10.12677/ACM.2023.1371700
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NOTES
*通讯作者。