腦動(dòng)脈瘤發(fā)病機(jī)制探討

1、腦動(dòng)脈瘤發(fā)病機(jī)制探討,譚華橋 MD PhD浙江省人民醫(yī)院神經(jīng)介入中心浙江省人民醫(yī)院卒中中心,上海. 2013.12,腦動(dòng)脈瘤定義,A brain aneurysm is a protruding bubble or sac on a blood vessel caused by a weak spot in the vessel wall that balloons out over time.,腦動(dòng)脈瘤患病率,尸檢研究：0.

2、2%- 9.9% (平均≈5%) 血管造影研究:3.7%-6.0% 回顧性薈萃研究:2%(排除成人多囊腎或動(dòng) 脈瘤性SAH家族史） 最新研究(Ann Intern Med)：7%（中國(guó)),動(dòng)脈瘤性SAH發(fā)病率和危害性,動(dòng)脈瘤性SAH發(fā)病率WHO研究發(fā)現(xiàn)歐洲和亞洲國(guó)家校正年齡年動(dòng)脈瘤性SAH發(fā)病率相差10倍（中國(guó)2/100000;芬蘭22.5/100000)最新的薈萃研究：動(dòng)脈瘤性SAH發(fā)病率2-16/100000,動(dòng)脈

3、瘤性SAH危害性 10-15%患者在入院接受治療前死亡 致死率高達(dá)40%～50%,致殘率高達(dá)10%～20%,動(dòng)脈瘤好發(fā)部位,腦動(dòng)脈瘤病理,內(nèi)彈力板缺乏,中膜平滑肌細(xì)胞凋亡減少，中膜變薄甚至連續(xù)性中斷 .,a=外膜 m=中膜, i =內(nèi)膜,eel=外彈力板 Iel=內(nèi)彈力板,腦動(dòng)脈瘤病理變化過(guò)程,內(nèi)皮功能紊亂,血管平滑肌細(xì)胞（VSMC)表型轉(zhuǎn)化,,細(xì)胞外基質(zhì)（ECM)重塑,,VSMC凋亡、血管退變,,VSMC凋亡、血管退變,

4、,局限性擴(kuò)張,,,動(dòng)脈瘤形成,生長(zhǎng)、破裂,,腦動(dòng)脈瘤發(fā)病因素,先天性或遺傳性因素腦血管解剖變異先天性中膜缺損 遺傳基因差異家族性顱內(nèi)動(dòng)脈瘤,后天性獲得因素血流動(dòng)力學(xué)環(huán)境因素，如吸煙、飲酒、高血壓、高脂血癥、雌激素、感染、創(chuàng)傷等,腦動(dòng)脈瘤發(fā)生-先天性或遺傳性因素,腦血管解剖變異Willis 環(huán)及腦動(dòng)脈系統(tǒng)常見的解剖形態(tài)學(xué)異常 雙側(cè)腦動(dòng)脈直徑的顯著差異 某些腦動(dòng)脈節(jié)段先天性缺如或發(fā)育不全 某些胚胎發(fā)育過(guò)程中

5、的原始動(dòng)脈通道( 如殘存的三叉動(dòng)脈、舌下動(dòng)脈等) 殘留 某些先天性腦血管疾病，如: MOYAMOYA病、AVM 等,腦動(dòng)脈瘤發(fā)生- 先天性或遺傳性因素,先天性中膜缺陷理論基礎(chǔ)： 腦主要?jiǎng)用}的分支部位動(dòng)脈壁存在中膜缺陷,而動(dòng)脈分叉是顱內(nèi)動(dòng)脈瘤的好發(fā)部位.理論缺陷：約80%的腦血管分叉部均存在中膜缺損, 而動(dòng)脈瘤的發(fā)病率卻遠(yuǎn)遠(yuǎn)低于這一水平. 動(dòng)脈瘤瘤壁組織中中膜結(jié)構(gòu)的損傷可能并非動(dòng)脈瘤形成時(shí)的始動(dòng)因素, 而是動(dòng)脈瘤發(fā)生、發(fā)

6、展的結(jié)果,腦動(dòng)脈瘤發(fā)生-先天性或遺傳性因素,遺傳基因證據(jù)常染色體顯性遺傳多囊腎疾病(ADPKD) 神經(jīng)纖維瘤病I型 馬凡氏綜合癥 多發(fā)性內(nèi)分泌瘤病 I型彈性假黃色瘤 遺傳性出血性毛細(xì)血管擴(kuò)張癥埃－當(dāng)綜合征 II 和 IV型,相關(guān)候選基因與細(xì)胞外基質(zhì)成分合成相關(guān)的基因:ELN（彈性蛋白）、COL（膠原蛋白）3A1、COL1A2、LOX、FBN2與細(xì)胞外基質(zhì)降解相關(guān)的多種蛋白酶編碼基因: MMPs、TIMPs、A1 ant

7、itrypsin COL1A2和ELN是最有可能與顱內(nèi)動(dòng)脈瘤等位遺傳基因相關(guān)的候選基因。,遺傳性因素,血流動(dòng)力學(xué)因素在腦動(dòng)脈瘤發(fā)生中發(fā)揮重要作用,腦動(dòng)脈瘤發(fā)生-后天獲得性因素,Stroke. 2002;33:1911-1915,方法：結(jié)扎雙側(cè)腎后動(dòng)脈誘發(fā)腎性高血壓+結(jié)扎單側(cè)頸總動(dòng)脈增加對(duì)側(cè)ACA-OA血流結(jié)果：增加的血流動(dòng)力學(xué)應(yīng)力和誘導(dǎo)高血壓能夠誘發(fā)大鼠實(shí)驗(yàn)性腦動(dòng)脈瘤形成,內(nèi)彈力板破壞和高血壓能夠誘發(fā)大鼠顱內(nèi)動(dòng)脈瘤形成，兩者在顱

8、內(nèi)動(dòng)脈瘤形成中具有協(xié)同效應(yīng),Hypertension. 2009;54:1337-1344,,Stroke. 2008;39:2085-2090,單獨(dú)增加血流動(dòng)力學(xué)損傷能夠誘發(fā)新生腦動(dòng)脈瘤，這種新生動(dòng)脈瘤破壞性重塑依賴于增加的血流,,Stroke. 2007;38:1924-1931,高的壁切應(yīng)力和切應(yīng)力梯度易于導(dǎo)致頂端動(dòng)脈瘤形成,,高的壁切應(yīng)力和正性切應(yīng)力梯度是誘發(fā)動(dòng)脈瘤樣重塑的危險(xiǎn)血流動(dòng)力學(xué),,Stroke. 2010;41:177

9、4-1782,,Neurosurgery 65:169–178, 2009,,,,,,,.bFGF =basic fibroblast growth factor; COX2=cyclooxygenase-2; ECM=extracellular matrix; ICAM=intercellular adhesion molecule; IL= interleukin; MCP=monocyte chemoattractan

10、t Protein MMP=matrix metalloproteinase; NK= natural killer; NO=nitric oxide; PGD= prostaglandin D; PGE= prostaglandin E;ROS= reactive oxygen species; TGF=transforming growth factor; TLR= toll-like receptor; TNF=

11、tumor necrosis factor; VCAM=vascular cell adhesion moleculeVEGF= vascular endothelial growth factor VSMC=vascular smooth muscle cell,Cerebral aneurysm (CA) formation and rupture.,Stroke. 2013;44:3613-3622.,Inflammator

12、y Pathways and Mediators Implicated in CA Formation and Rupture,Stroke. 2013;44:3613-3622.,Inflammatory Pathways and Mediators Implicated in CA Formation and Rupture,Stroke. 2013;44:3613-3622.,IL-1β indicates interleukin

13、 1β; KLF-4, Kruppel-like transcription factor 4; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase;NF-κB, nuclear factor-κ B; SMC, smooth muscle cell; and TNFα, tumornecrosis factor-α.,C, complemen

14、t system; C3a and C5a, anaphylatoxins; CRP, C reactive protein; EC, endothelial cell; IFN-g, interferon gamma; IgG, immunoglobulin G; IgM, immunoglobulin M; IL-1b, interleukin 1-beta; Mø, macrophage; MCP-1, monocyte

15、 chemotactic protein; MHC-I and MHC-II, major histocompability complexes I and I; MMP, matrix metalloproteinase; NK, natural killer cell; RNS, reactive nitrogen species; ROS, reactive oxygen species; SCR, scavenger recep

16、tor; SMC, smooth muscle cell; T, T cell; TGF-b, tissue growth factor beta; TNF-a, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1.,Probable activators and main functions of macrophages in intracran

17、ial aneurysms.,probable activation mechanisms and functions of adaptive immunity in intracranial aneurysms,Cytokines and inflammatory mediators Interferon gamma, IFN-g; Tumor necrosis factor alpha and beta, TNF-a and T

18、NF-b; Interleukins, IL,MHC= major histocompability complexTCR =T cell receptor Mø = macrophage T cell recognizes the Th =CD4 (helper T cells,) Tc = CD8 (cytotoxic T cells) NK =Natural killer,Journal of

19、Cerebral Blood Flow & Metabolism (2012) 32, 1659–1676,Vascular smooth muscle cells (VSMCs) in intracranial aneurysm (IA) wall. Phenotypic modulation of VSMC from a contractile to pro-inflammatory/pro-matrix remodelin

20、g phenotype within the aneurysm wall leads to myointimal hyperplasia, inflammation, and vessel wall degeneration. Subsequent apoptosis and VSMC death lead to a hypocellular thin wall with increased IA susceptibility to r

21、upture. SM-MHC, smooth muscle-myosin heavy chain; SM-α-actin, smooth muscle-α-actin; SSAO, semicarbazide-sensitive amine oxidase; NO, nitric oxide; TNFα, tumor necrosis factor-α; MCP1, monocyte chemoattractant protein 1;

22、 IL1β, Interleukin 1β; ROS, reactive oxygen species; MMPs, matrix metalloproteinases.,Stroke. 2009;40:942-951,MCP-1在動(dòng)脈瘤形成早期階段表達(dá)上調(diào)， MCP-1基因敲出的大鼠動(dòng)脈瘤形成下降、巨噬細(xì)胞聚集下降，MMP-2和MMP-9、iNOS表達(dá)下降，在MCP-1表達(dá)的細(xì)胞中顯示NF- kappa-β激活。阻止MCP-1激活則抑

23、制動(dòng)脈瘤形成。MCP-1作為單核/巨噬細(xì)胞趨化因子在動(dòng)脈瘤形成中起關(guān)鍵作用，MCP-1在動(dòng)脈瘤壁表達(dá)通過(guò)NF- kappa-β激活。,Circulation. 2007;116:2830-2840,NF- ?通過(guò)誘發(fā)一些同巨噬細(xì)胞聚集和激活的炎癥基因在腦動(dòng)脈瘤形成中發(fā)揮重要作用,增加的TNF 和FAS相關(guān)死亡域蛋白通過(guò)促進(jìn)血管和免疫細(xì)胞炎癥反應(yīng)和隨后的凋亡對(duì)腦動(dòng)脈施加有害影響，消弱血管壁。,Neurosurgery 57:558-56

24、4, 2005,Schematic model for TNF signaling in cerebral aneurysm,TNF may participate in the inflammatory, apoptotic, and vessel destructive processes in cerebral aneurysms by promoting the synthesis of IL-1, IL-6, FADD pro

25、tein, and metalloproteinases (MMPs), respectively. Activation of these proinflammatory proteins from leukocytes, and tissuedegrading enzymes associated with apoptosis, may weaken the arterial wall, leading to aneurysm fo

26、rmation and rupture. However, IL-10 expression may negatively modulate TNF and inhibit TNF-associatedinflammation,PLoS ONE 8(9): e74357. doi:10.1371/journal.pone.0074357,在血流動(dòng)力學(xué)觸發(fā)的動(dòng)脈瘤起始階段，SMC而不是巨噬細(xì)胞負(fù)責(zé)動(dòng)脈瘤樣病變發(fā)展的關(guān)鍵炎癥介質(zhì)-MMP生產(chǎn)

27、,ROS生成基因p47phox在動(dòng)脈瘤壁炎性浸潤(rùn)的巨噬細(xì)胞和SMC上調(diào)，上調(diào)的ROS 生成基因和抑制的ROS清除基因提示ROS在動(dòng)脈瘤壁生成過(guò)量。自由基吞噬體通過(guò)抑制炎癥相關(guān)基因表達(dá)有效抑制動(dòng)脈瘤形成，而且p47phox敲出的大鼠動(dòng)脈瘤形成受抑制，動(dòng)脈瘤壁炎癥反應(yīng)下降。ROS和ROS p47phox 積極參與腦動(dòng)脈瘤的形成,Laboratory Investigation (2009) 89, 730–741,Circulation.

28、 2000;101:2532-2538,Curr Neurovasc Res. 2013; 10(3): 247–255.,Potential mediators of oxidative stress in cerebral aneurysm pathogenesis.,CS increases wall shear stress in cerebral vessels and causes endothelial dysfuncti

29、on with VSMC proinflammatory phenotypic modulation. The resultant inflammatory response implicates several inflammatory cells and mediators (ROS in particular) and leads to extracellular matrix remodeling and subsequent

30、aneurysm formation. Further CSinduced matrix breakdown, cell death, and formation of an organizing thrombus eventually culminate in CA rupture.,Mediators of Inflammation 2012, doi:10.1155/2012/271582,Cigarette Smoke an

31、d Inflammation: Role in Cerebral Aneurysm Formation and Rupture,Mediators of Inflammation 2012, doi:10.1155/2012/271582,Medical Hypotheses (2006) 66, 736–756,Hypertension. 2009;54:552-557,鹽皮質(zhì)激素受體阻滯劑通過(guò)抑制氧化應(yīng)激、炎癥因子、局部腎素-血

32、管緊張素系統(tǒng)活性和鹽攝入抑制腦動(dòng)脈瘤形成， 提示鹽皮質(zhì)激素受體激活至少部分參與腦動(dòng)脈瘤發(fā)病機(jī)制,Laboratory Investigation (2011) 91, 619–626,動(dòng)脈瘤形成部位eNOS表達(dá)下降， eNOS基因敲除大鼠動(dòng)脈瘤發(fā)生率與野生型類似。在在eNOS基因敲除的大鼠，nNOS表達(dá)上調(diào)，提示nNOS補(bǔ)償作用。而eNOS和nNOS基因同時(shí)敲除的大鼠動(dòng)脈瘤形成發(fā)生率增加eNOS和nNOSeNOS在腦動(dòng)脈缺陷能夠?yàn)閚N