血流动力学影响动脉瘤壁重构对颅内动脉瘤破裂的作用和机制

Hemodynamic factors and wall remodeling of aneurysm have been associated with rupture of cerebral aneurysms. Ruptured cerebral aneurysm is characterized significant loss of internal elastic lamina, increased inflammation reaction, large loss of smooth muscle cells in our previous studies, and aneurysm also has low wall shear stress and complex mechanical prameters. We suspect that aneurysmal wall cell transduces stimuli of hemodynamic forces into biochemical signals, which modulate secretion of cytokines and exacerbate progressing wall remodeling, leading to wall weakness and final rupture. Hemodynamics-biology co-mapping technique enables in the connection between the specific hemodynamic microenvironment and vascular remodeling. In this study, geometric parameters of ruptured aneurysm are assessed based on three dimensional digital subtraction angiographic images. These images are used to perform patient-specific computational fluid-structure interaction simulation. Meanwhile, one segment of aneurysm wall is analyzed by Protein microarray analysis, and other segement is obtained for immunohistochemistry and immunofluorescence staining. Furthermore, the hemodynamic field inside aneurysm is virtually sectioned based on the histological slicing planes. Simulative fluid images are digitally co-mapped with histological images. The connection of mechanical stimuli and vascular remodeling will be determined, and molecular mechanism underlying rupture of aneurysm will be also recognized. This study provides a new target biomarker for potential interventinal strategy to prevent aneruysm from rupturing.

颅内动脉瘤破裂与血流动力学和动脉瘤壁重构密切相关。我们前期发现破裂动脉瘤存在大量炎性细胞浸润，伴金属基质蛋白酶（MMPs）异常表达增高，并且动脉瘤壁面切应力分布不同，推测动脉瘤破裂是通过特定血流动力刺激动脉瘤壁细胞，这些细胞分泌细胞因子，促进瘤壁进行性重构来实现。该课题应用生物力学映射技术关联动脉瘤流体力学与分子病理来验证该假设，阐释具体机制。实验拟收集手术治疗的破裂与未破裂动脉瘤三维影像数据，以建立患者特定的流固耦合血流动力学模型，模拟两组动脉瘤几何形态相关的血流动力学参数，分析动脉瘤破裂的血流动力学机制；然后，取部分瘤壁进行蛋白组学筛选动脉瘤破裂的特异蛋白，部分瘤壁进行病理组织学研究，将动脉瘤血流动力学参数分布图与瘤壁免疫荧光图像数字融合，研究血流动力学影响动脉瘤壁进行性重构的作用，进一步筛选和验证动脉瘤破裂的分子机制，为预防或延缓动脉瘤破裂提供新的干预靶点，降低动脉瘤破裂的风险。

目前的研究认为颅内动脉瘤破裂的机制主要涉及动脉瘤内部的异常血流动力学环境和动脉瘤壁病理改变这两个方面。二者作为影响动脉瘤破裂的重要因素，其之间也存在相互作用。该作用会导致动脉瘤产生一系列恶性循环，加速瘤壁损伤并最终导致动脉瘤破裂。本课题的申请者长期从事颅内动脉瘤的神经外科干预治疗，并不断积极探索颅内动脉瘤的破裂机制，一直致力于寻找预防和延缓颅内动脉瘤破裂的干预靶点。我们的前期研究发现异常的血流动力学可以加重动脉瘤壁的损伤，促进炎症因子的大量表达。该过程可能是诱导动脉瘤壁重构发生的重要病理机制。本研究拟在前期研究的基础上，结合分析颅内动脉瘤的血流动力学特点和瘤壁组织病理表现及分子表达特点的差异，运用生物力学映射的分析方法，达到以下目标：1. 阐明动脉瘤破裂的血流动力学机制；2. 对破裂动脉瘤的分子机制进行了分析；3. 明确血流动力学因素与动脉瘤壁重构之间的相互关系及其对动脉瘤破裂的影响；4. 阐明动脉瘤内血流动力学因素影响瘤壁重构的可能机制；5. 筛选出新的预防或延缓动脉瘤破裂的可能干预靶点。本研究将为建立更为准确颅内动脉瘤破裂风险预测方法和颅内动脉瘤新干预靶点的探索提供重要的理论基础。