脑动脉瘤发病机制探讨

1、脑动脉瘤发病机制探讨谭华桥 MD PhD浙江省人民医院神经介入中心浙江省人民医院卒中中心上海. 2013.12脑动脉瘤定义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. 脑动脉瘤患病率o 尸检研究：0.2%- 9.9% (平均5%) o 血管造影研究:3.7%-6.0%o 回顾性荟萃研究:2%(排除成人多囊肾或动 脉瘤性SAH家族史）o 最新研究(Ann Intern Med

2、)：7%（中国) 动脉瘤性SAH发病率和危害性 动脉瘤性SAH发病率 WHO研究发现欧洲和亚洲国家校正年龄年动脉瘤性SAH发病率相差10倍（中国2/100000;芬兰22.5/100000) 最新的荟萃研究：动脉瘤性SAH发病率2-16/100000动脉瘤性SAH危害性 10-15%患者在入院接受治疗前死亡 致死率高达40%50%,致残率高达10%20% 动脉瘤好发部位脑动脉瘤病理内弹力板缺乏,中膜平滑肌细胞凋亡减少，中膜变薄甚至连续性中断 . a=外膜 m=中膜, i =内膜,eel=外弹力板 Iel=内弹力板脑动脉瘤病理变化过程内皮功能紊乱血管平滑肌细胞（VSMC)表型转化细胞外基质（EC

3、M)重塑VSMC凋亡、血管退变 VSMC凋亡、血管退变 局限性扩张动脉瘤形成生长、破裂脑动脉瘤发病因素先天性或遗传性因素先天性或遗传性因素o 脑血管解剖变异脑血管解剖变异o 先天性中膜缺损先天性中膜缺损 o 遗传基因差异遗传基因差异o 家族性颅内动脉瘤家族性颅内动脉瘤后天性获得因素后天性获得因素o 血流动力学血流动力学o 环境因素，如吸烟、饮酒、环境因素，如吸烟、饮酒、高血压、高脂血症、雌激高血压、高脂血症、雌激素、感染、创伤等素、感染、创伤等 脑动脉瘤发生-先天性或遗传性因素脑血管解剖变异uWillis 环及脑动脉系统常见的解剖形态学异常 双侧脑动脉直径的显著差异 某些脑动脉节段先天性缺如或

4、发育不全 u某些胚胎发育过程中的原始动脉通道( 如残存的三叉动脉、舌下动脉等) 残留 u某些先天性脑血管疾病，如: MOYAMOYA病、AVM 等脑动脉瘤发生- 先天性或遗传性因素先天性中膜缺陷u理论基础： 脑主要动脉的分支部位动脉壁存在中膜缺陷,而动脉分叉是颅内动脉瘤的好发部位.u理论缺陷：约80%的脑血管分叉部均存在中膜缺损, 而动脉瘤的发病率却远远低于这一水平. 动脉瘤瘤壁组织中中膜结构的损伤可能并非动脉瘤形成时的始动因素, 而是动脉瘤发生、发展的结果 脑动脉瘤发生-先天性或遗传性因素遗传基因证据l 常染色体显性遗传多囊肾疾病(ADPKD) l 神经纤维瘤病I型 l 马凡氏综合症 l 多

5、发性内分泌瘤病 I型l 弹性假黄色瘤 l 遗传性出血性毛细血管扩张症l 埃当综合征 II 和 IV型相关候选基因l 与细胞外基质成分合成相关的基因:ELN（弹性蛋白）、COL（胶原蛋白）3A1、COL1A2、LOX、FBN2l 与细胞外基质降解相关的多种蛋白酶编码基因: MMPs、TIMPs、A1 antitrypsin COL1A2和ELN是最有可能与颅内动脉瘤等位遗传基因相关的候选基因。遗传性因素血流动力学因素在脑动脉瘤发生中发挥重要作用血流动力学因素在脑动脉瘤发生中发挥重要作用脑动脉瘤发生-后天获得性因素 Stroke. 2002;33:1911-1915方法：结扎双侧肾后动脉诱发肾性高

6、血压+结扎单侧颈总动脉增加对侧ACA-OA血流结果：增加的血流动力学应力和诱导高血压能够诱发大鼠实验性脑动脉瘤形成内弹力板破坏和高血压能够诱发大鼠颅内动脉瘤形成，两者在颅内动脉瘤形成中具有协同效应Hypertension. 2009;54:1337-1344 Stroke. 2008;39:2085-2090单独增加血流动力学损伤能够诱发新生脑动脉瘤，这种新生动脉瘤破坏性重塑依赖于增加的血流Stroke. 2007;38:1924-1931 高的壁切应力和切应力梯度易于导致顶端动脉瘤形成高的壁切应力和正性切应力梯度是诱发动脉瘤样重塑的危险血流动力学 Stroke. 2010;41:1774-1

7、782Neurosurgery 65:169178, 2009.bFGF =basic fibroblast growth factor; COX2=cyclooxygenase-2; ECM=extracellular matrix; ICAM=intercellular adhesion molecule; IL= interleukin; MCP=monocyte chemoattractant Protein MMP=matrix metalloproteinase; NK= natural killer; NO=nitric oxide; PGD= prostaglandin D;

8、PGE= prostaglandin E;ROS= reactive oxygen species; TGF=transforming growth factor; TLR= toll-like receptor; TNF=tumor necrosis factor; VCAM=vascular cell adhesion moleculeVEGF= vascular endothelial growth factor VSMC=vascular smooth muscle cell Cerebral aneurysm (CA) formation and rupture.Stroke. 20

9、13;44:3613-3622.PathwayMediatorsPathwayMediatorsEndothelial dysfunctionIL-1NF-BEts-1MCP-1Reactive oxygen speciesNitric oxide (NO), endothelial NO synthase, inducible NO synthaseAngiotensin IIPhosphodiesterase-4Prostaglandin E2E selectin, P selectin, vascular cell adhesion protein 1 (VCAM1), Intercel

10、lular adhesion molecule 1 (ICAM1)Macrophages, M1/M2 imbalance, leukocyte infiltrationMCP-1IL-17IL-8EotaxinTNF-IL-1MMPsEts-1NF-BNormal T cell expressed and secretedMonokine induced by -interferonInterferon-induced protein-10Inflammatory Pathways and Mediators Implicated in CA Formation and RuptureStr

11、oke. 2013;44:3613-3622.PathwayMediatorsPathwayMediatorsPhenotypic modulation andloss of SMCsTNF-Adhesion moleculesMMPsMCP-1P47phoxIL-1KLF-4Vascular remodeling, Cell deathMMP and cathepsinsTNFIL-1, IL-6Toll-like receptor 4FasNOComplement IgG, IgMBasic fibroblast growth factorTransforming growth facto

12、r and Vascular endothelial growth factorReactive oxygen speciesInflammatory Pathways and Mediators Implicated in CA Formation and RuptureStroke. 2013;44:3613-3622.IL-1 indicates interleukin 1; KLF-4, Kruppel-like transcription factor 4; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metallop

13、roteinase;NF-B, nuclear factor- B; SMC, smooth muscle cell; and TNF, tumornecrosis factor-.C, complement 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; M, macrophage

14、; MCP-1, monocyte 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 receptor; SMC, smooth muscle cell; T, T cell; TGF-b, tissue growth f

15、actor beta; TNF-a, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1.Probable activators and main functions of macrophages in intracranial bable activation mechanisms and functions of adaptive immunity in intracranial aneurysms巨噬细胞或其他抗原呈递细胞抗原组织相容性抗原复合物组织相容性抗原复合物Cyto

16、kines and inflammatory mediators Interferon gamma, IFN-g; Tumor necrosis factor alpha and beta, TNF-a and TNF-b; Interleukins, ILMHC= major histocompability complexTCR =T cell receptor M = macrophage T cell recognizes the Th =CD4 (helper T cells,) Tc = CD8 (cytotoxic T cells) NK =Natural killerJourn

17、al of Cerebral Blood Flow & Metabolism (2012) 32, 16591676Vascular smooth muscle cells (VSMCs) in intracranial aneurysm (IA) wall. Phenotypic modulation of VSMC from a contractile to pro-inflammatory/pro-matrix remodeling phenotype within the aneurysm wall leads to myointimal hyperplasia, inflammati

18、on, and vessel wall degeneration. Subsequent apoptosis and VSMC death lead to a hypocellular thin wall with increased IA susceptibility to rupture. SM-MHC, smooth muscle-myosin heavy chain; SM-actin, smooth muscle-actin; SSAO, semicarbazide-sensitive amine oxidase; NO, nitric oxide; TNF, tumor necro

19、sis factor-; MCP1, monocyte chemoattractant protein 1; IL1, Interleukin 1; ROS, reactive oxygen species; MMPs, matrix metalloproteinases.Stroke. 2009;40:942-951MCP-1在动脉瘤形成早期阶段表达上调， MCP-1基因敲出的大鼠动脉瘤形成下降、巨噬细胞聚集下降，MMP-2和MMP-9、iNOS表达下降，在MCP-1表达的细胞中显示NF- kappa-激活。阻止MCP-1激活则抑制动脉瘤形成。MCP-1作为单核/巨噬细胞趋化因子在动脉瘤形成

20、中起关键作用，MCP-1在动脉瘤壁表达通过NF- kappa-激活。Circulation. 2007;116:2830-2840NF- 通过诱发一些同巨噬细胞聚集和激活的炎症基因在脑动脉瘤形成中发挥重要作用 增加的TNF 和FAS相关死亡域蛋白通过促进血管和免疫细胞炎症反应和随后的凋亡对脑动脉施加有害影响，消弱血管壁。Neurosurgery 57:558-564, 2005Schematic model for TNF signaling in cerebral aneurysmTNF may participate in the inflammatory, apoptotic, and

21、vessel destructive processes in cerebral aneurysms by promoting the synthesis of IL-1, IL-6, FADD protein, and metalloproteinases (MMPs), respectively. Activation of these proinflammatory proteins from leukocytes, and tissuedegrading enzymes associated with apoptosis, may weaken the arterial wall, l

22、eading to aneurysm formation and rupture. However, IL-10 expression may negatively modulate TNF and inhibit TNF-associatedinflammationPLoS ONE 8(9): e74357. doi:10.1371/journal.pone.0074357在血流动力学触发的动脉瘤起始阶段，SMC而不是巨噬细胞负责动脉瘤样病变发展的关键炎症介质-MMP生产ROS生成基因p47phox在动脉瘤壁炎性浸润的巨噬细胞和SMC上调，上调的ROS 生成基因和抑制的ROS清除基因提示RO

23、S在动脉瘤壁生成过量。自由基吞噬体通过抑制炎症相关基因表达有效抑制动脉瘤形成，而且p47phox敲出的大鼠动脉瘤形成受抑制，动脉瘤壁炎症反应下降。ROS和ROS p47phox 积极参与脑动脉瘤的形成Laboratory Investigation (2009) 89, 730741Circulation. 2000;101:2532-2538Curr Neurovasc Res. 2013; 10(3): 247255.Potential mediators of oxidative stress in cerebral aneurysm pathogenesis.CS increases

24、wall shear stress in cerebral vessels and causes endothelial dysfunction 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 aneurysm formation.