脑动脉瘤发病机制探讨

脑动脉瘤发生- 先天性或遗传性因素
先天性中膜缺陷
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. 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
Stroke. 2013;44:3613-3622.
Inflammatory Pathways and Mediators Implicated in CA Formation and Rupture
Pathway Endothelial dysfunction Mediators IL-1β NF-κB Ets-1 MCP-1 Reactive oxygen species Nitric oxide (NO), endothelial NO synthase, inducible NO synthase Angiotensin II Phosphodiesterase-4 Prostaglandin E2 E selectin, P selectin, vascular cell adhesion protein 1 (VCAM1), Intercellular adhesion molecule 1 (ICAM1) Pathway Macrophages, M1/M2 imbalance, leukocyte infiltration Mediators MCP-1 IL-17 IL-8 Eotaxin TNF-α IL-1β MMPs Ets-1 NF-κB Normal T cell expressed and secreted Monokine induced by γ-interferon Interferon-γ–induced protein-10
Stroke. 2013;44:3613-3622.
Probable activators and main functions of macrophages in intracranial aneurysms.
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; Mø , macrophage; 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 factor beta; TNF-a, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1.
IL-1β indicates interleukin 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.
脑动脉瘤发生-后天获得性因素
血流动力学因素在脑动脉瘤发生中发挥重要作用
方法：结扎双侧肾后动脉诱发肾性高血压+结扎单侧颈总动脉增加对侧ACAOA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 Stroke. 2002;33:1911-1915
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
脑动脉瘤患病率
尸检研究：0.2%- 9.9% (平均≈5%) 血管造影研究:3.7%-6.0% 回顾性荟萃研究:2%(排除成人多囊肾或动 脉瘤性SAH家族史） 最新研究(Ann Intern Med)：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
Stroke. 2013;44:3613-3622.
Inflammatory Pathways and Mediators Implicated in CA Formation and Rupture
Pathway Phenotypic modulation and loss of SMCs Mediators TNF-α Adhesion molecules MMPs MCP-1 P47phox IL-1β KLF-4 Pathway Vascular remodeling, Cell death Mediators MMP and cathepsins TNFα IL-1β, IL-6 Toll-like receptor 4 Fas NO Complement IgG, IgM Basic fibroblast growth factor Transforming growth factor α and β Vascular endothelial growth factor Reactive oxygen species
脑动脉瘤发生-先天性或遗传性因素
遗传性因素
遗传基因证据
常染色体显性遗传多囊肾疾病 (ADPKD) 神经纤维瘤病I型 马凡氏综合症 多发性内分泌瘤病 I型 弹性假黄色瘤 遗传性出血性毛细血管扩张症 埃－当综合征 II 和 IV型
相关候选基因
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、FBN2 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。
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 .
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（ECM)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 脑血管解剖变异 先天性中膜缺损 遗传基因差异 家族性颅内动脉瘤 后天性获得因素 血流动力学 环境因素，如吸烟、饮酒、 高血压、高脂血症、雌激 素、感染、创伤等
抗原
巨噬细胞或其他 抗原呈递细胞
组织百度文库容 性抗原复 合物
组织相容 性抗原复 合物
Cytokines and inflammatory mediators Interferon gamma, IFN-g; Tumor necrosis factor alpha and beta, TNF-a and TNF-b; Interleukins, IL
probable activation mechanisms and functions of adaptive immunity in intracranial aneurysms
MHC= major histocompability complex TCR =T cell receptor Mø = macrophage T cell recognizes the Th =CD4 (helper T cells,) Tc = CD8 (cytotoxic T cells) NK =Natural killer
动脉瘤性SAH危害性
10-15%患者在入院接受治疗前 死亡
差10倍（中国2/100000;芬兰
22.5/100000) 最新的荟萃研究：动脉瘤性SAH
致死率高达40%～50%,致残率高
达10%～20%
发病率2-16/100000
动脉瘤好发部位
脑动脉瘤病理
a=外膜 m=中膜, i =内膜, eel=外弹力板 Iel=内弹力板
Neurosurgery 65:169–178, 2009
Cerebral aneurysm (CA) formation and rupture.
.
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; PGE= prostaglandin E; ROS= reactive oxygen species; TGF=transforming growth factor; TLR= toll-like receptor; TNF=tumor necrosis factor; VCAM=vascular cell adhesion molecule VEGF= vascular endothelial growth factor VSMC=vascular smooth muscle cell
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.
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. 2008;39:2085-2090
高的壁切应力和切应力梯度易于导致顶端动脉瘤形成 Stroke. 2007;38:1924-1931
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;41:1774-1782
脑动脉瘤发生-先天性或遗传性因素
脑血管解剖变异
Willis 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发育不全 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 某些先天性脑血管疾病，如: MOYAMOYA病、AVM 等
Vascular smooth muscle cells (VSMCs) in intracranial aneurysm (IA) wall. Phenotypic modulation of VSMC from a contractile to proinflammatory/pro-matrix remodeling 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 rupture. 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; IL1β, Interleukin 1β; ROS, reactive oxygen species; MMPs, matrix metalloproteinases.