腦動脈瘤發(fā)病機制探討

1、腦動脈瘤發(fā)病機制探討,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 脈瘤性SAH家族史） 最新研究(Ann Intern Med)：7%（中國),動脈瘤性SAH發(fā)病率和危害性,動脈瘤性SAH發(fā)病率WHO研究發(fā)現(xiàn)歐洲和亞洲國家校正年齡年動脈瘤性SAH發(fā)病率相差10倍（中國2/100000;芬蘭22.5/100000)最新的薈萃研究：動脈瘤性SAH發(fā)病率2-16/100000,動脈

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40%～50%,致殘率高達10%～20%,動脈瘤好發(fā)部位,腦動脈瘤病理,內(nèi)彈力板缺乏,中膜平滑肌細胞凋亡減少，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,腦動脈瘤病理變化過程,內(nèi)皮功能紊亂,血管平滑肌細胞（VSMC)表型轉(zhuǎn)化,,細胞外基質(zhì)（ECM)重塑,,VSMC凋亡、血管退變,,VSMC凋亡、血管退變,

4、,局限性擴張,,,動脈瘤形成,生長、破裂,,腦動脈瘤發(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)動脈瘤,后天性獲得因素血流動力學(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)及腦動脈系統(tǒng)常見的解剖形態(tài)學(xué)異常 雙側(cè)腦動脈直徑的顯著差異 某些腦動脈節(jié)段先天性缺如或發(fā)育不全 某些胚胎發(fā)育過程中

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

6、展的結(jié)果,腦動脈瘤發(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 遺傳性出血性毛細血管擴張癥埃－當(dāng)綜合征 II 和 IV型,相關(guān)候選基因與細胞外基質(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)動脈瘤等位遺傳基因相關(guān)的候選基因。,遺傳性因素,血流動力學(xué)因素在腦動脈瘤發(fā)生中發(fā)揮重要作用,腦動脈瘤發(fā)生-后天獲得性因素,Stroke. 2002;33:1911-1915,方法：結(jié)扎雙側(cè)腎后動脈誘發(fā)腎性高血壓+結(jié)扎單側(cè)頸總動脈增加對側(cè)ACA-OA血流結(jié)果：增加的血流動力學(xué)應(yīng)力和誘導(dǎo)高血壓能夠誘發(fā)大鼠實驗性腦動脈瘤形成,內(nèi)彈力板破壞和高血壓能夠誘發(fā)大鼠顱內(nèi)動脈瘤形成，兩者在顱

8、內(nèi)動脈瘤形成中具有協(xié)同效應(yīng),Hypertension. 2009;54:1337-1344,,Stroke. 2008;39:2085-2090,單獨增加血流動力學(xué)損傷能夠誘發(fā)新生腦動脈瘤，這種新生動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)動脈瘤樣重塑的危險血流動力學(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在動脈瘤形成早期階段表達上調(diào)， MCP-1基因敲出的大鼠動脈瘤形成下降、巨噬細胞聚集下降，MMP-2和MMP-9、iNOS表達下降，在MCP-1表達的細胞中顯示NF- kappa-β激活。阻止MCP-1激活則抑

23、制動脈瘤形成。MCP-1作為單核/巨噬細胞趨化因子在動脈瘤形成中起關(guān)鍵作用，MCP-1在動脈瘤壁表達通過NF- kappa-β激活。,Circulation. 2007;116:2830-2840,NF- ?通過誘發(fā)一些同巨噬細胞聚集和激活的炎癥基因在腦動脈瘤形成中發(fā)揮重要作用,增加的TNF 和FAS相關(guān)死亡域蛋白通過促進血管和免疫細胞炎癥反應(yīng)和隨后的凋亡對腦動脈施加有害影響，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,在血流動力學(xué)觸發(fā)的動脈瘤起始階段，SMC而不是巨噬細胞負(fù)責(zé)動脈瘤樣病變發(fā)展的關(guān)鍵炎癥介質(zhì)-MMP生產(chǎn)

27、,ROS生成基因p47phox在動脈瘤壁炎性浸潤的巨噬細胞和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在動脈瘤壁生成過量。自由基吞噬體通過抑制炎癥相關(guān)基因表達有效抑制動脈瘤形成，而且p47phox敲出的大鼠動脈瘤形成受抑制，動脈瘤壁炎癥反應(yīng)下降。ROS和ROS p47phox 積極參與腦動脈瘤的形成,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脈瘤形成， 提示鹽皮質(zhì)激素受體激活至少部分參與腦動脈瘤發(fā)病機制,Laboratory Investigation (2011) 91, 619–626,動脈瘤形成部位eNOS表達下降， eNOS基因敲除大鼠動脈瘤發(fā)生率與野生型類似。在在eNOS基因敲除的大鼠，nNOS表達上調(diào)，提示nNOS補償作用。而eNOS和nNOS基因同時敲除的大鼠動脈瘤形成發(fā)生率增加eNOS和nNOSeNOS在腦動脈缺陷能夠為nN