颅内动脉瘤模型的建立及血流动力学诱导瘤壁重构机制研究

Intracranial aneurysm, which was defined as the evection of intracranial artery, is one of the most leading causes of morbidity and mortality due to its rupture. The attack rate of aneurysm is about 2-5% in population and the mortality is about 40% with aneurysimal subarachnoid hemorrhage. Haemodynamics change due to hypertension and thin of aneurysm wall were the two leading causes of aneurysm rupture.It is important for preventing rupture of intracranial aneurysm by exploring the destructive remodeling of aneurysm wall by haemodynamics.On the basis of our previous aneurysm model of carotid artery in canine, we aim to construct an intracrainal aneurysm model and to explore the mechanisms of vascular remodeling of aneurysm wall during aneurysm progress.Artificial hypertentsion, ligation of carotid artery and digestion of IEL were used to construct aneurysm model. DSA/MRA and histology staining were used to monitoring formation and enlargement of aneurysm. Meanwhile, 3-D DSA, color Doppler and histology staining were combined to construct computor fluid dynamics model and to research the vascular remodeling in aneurysm wall of basilar terminus and its underlying mechanisms. To observe the the wall shear stress on the phenotype modulation of vascular smooth muscle cells (VSMC),a co-culture model of VSMC combined with WSS was constructed and the role of WSS on phenotype switching of VSMC and its mechanisms were detected. The present study aim to elucidate the growth characteristic of aneurysm and molecular mechanisms of vascular remodeling by haemodynamics. The results will provied bases for the animal model and insight into the mechanisms for preventing rupture of intracranial aneurysm.

颅内动脉瘤是常见的脑血管疾病，人群罹患率约2-5%。动脉瘤破裂出血的死亡率高达40%，目前尚无有效的预防其破裂的措施。缺少能够真实模拟人类动脉瘤特征的动物模型是探索预防动脉瘤破裂手段的"瓶颈"之一，建立一种既能连续观察动脉瘤生长特性、又能用于探讨动脉瘤破裂相关机制的模型，具有重要的科学意义。本研究构建犬颅内动脉瘤模型，并探讨血流动力学诱导动脉瘤壁损伤性重构的机制。采用人工高血压、颈内动脉结扎以及弹力酶消化弹力板等技术，制作颅内动脉瘤模型，影像学与组织学观察动脉瘤生长情况；应用3D-DSA、彩色多普勒及组织学技术，建立流体力学模型，研究血流剪切力对瘤壁的重构作用与机制；离体建立血管平滑肌细胞（VSMC）血流剪切力作用模型，观察血流剪切力对VSMC表型转化的作用与机制。本研究为阐明人类动脉瘤生长特性与破裂的相关机制，预防动脉瘤破裂出血及生物学治疗，奠定模型基础与理论基础。

颅内动脉瘤是神经外科高发病率脑血管疾病且破裂出血死亡率高达40 %。建立能够模拟人类动脉瘤特征的动物模型及探讨动脉瘤发生发展相关机制对于预防动脉瘤破裂具有重要临床意义。本研究通过采用人工高血压、颈内动脉结扎以及弹力酶消化等技术构建小鼠颅内动脉瘤模型，并在形态学与组织学建立评价体系。深入研究在动脉瘤形成过程中的作用机制，发现血管平滑肌的表型转化在其中起着关键性作用，通过阿司匹林干预血管平滑肌表型转化可降低动脉瘤的形成率并减少动脉瘤破裂风险。另外，高血流动力与颅内动脉瘤成瘤率、体积及破裂率有关，高血流动力学诱导平滑肌细胞表型转化在其中起着重要作用。进一步研究表明，mTOR信号通路、细胞外基质的破坏及炎症与高血流动力学诱导的血管表型转化有关。针对颅内动脉瘤破裂出血后脑损伤的相关机制进行深入研究，我们发现XIAP在颅内动脉瘤破裂出血后的凋亡机制中起着重要作用。针对性干预后血脑屏障、神经功能评分及脑水肿程度等均有明显改善。另外，发现氧合血红蛋白诱导的颅内动脉瘤破裂出血后基底动脉血管痉挛模型中NF-κB信号通路起着重要作用并与内皮素1的表达有关，抑制NF-κB信号通路可明显改善脉瘤破裂出血后基底动脉血管痉挛模型中的血管收缩程度。本研究为阐明人类动脉瘤生长特性与破裂出血的相关机制，预防动脉瘤破裂出血、改善动脉瘤破裂出血后症状并进行生物学治疗，奠定模型基础与理论基础。