Hemodynamic Induction of Pathologic Remodeling Leading to Intracranial Aneurysms

描述(申请人提供)：对颅内动脉瘤(IA)的形成知之甚少。我们认为特定的血流动力学条件对IA的形成是至关重要的，这在以前的动脉瘤模型中没有得到评估。利用兔IA模型，本项目试图确定这些导致动脉瘤形成的特定血流动力学条件，并确定在引发动脉瘤的病理性血管重塑中的关键分子反应。我们假设：1)以高壁切应力(WSS)和壁切应力梯度(WSSG)为特征的脑血管分叉处的异常血流动力学导致动脉瘤的破坏性重塑；2)这种病理反应是通过局部血流动力学刺激一氧化氮(NO)的产生和基质金属蛋白酶(MMPs)的活性来实现的。我们将评估这种IAS血流动力学启动的剂量依赖性，并使用计算流体动力学(CFD)来绘制启动血流动力学图。这将确定导致BT动脉瘤的特定血流动力学条件，并允许后续实验检查在动脉瘤形成之前对IA启动的血流动力学的生物学反应。然后，我们将检测在动脉瘤形成的早期阶段，血流动力学引起的一氧化氮产生和基质金属蛋白酶活性的变化。一氧化氮和基质金属蛋白酶在IAS血流动力学诱导中的作用将通过对这些分子的药理学操作来测试。目的1.确定引起流动诱导的IA的特定血流动力学条件。目的2.探讨MMPs在IAS血流动力学启动中的作用。目的3.确定诱导型一氧化氮合酶在调节IAS血流动力学启动中的作用。意义：IA破裂与高死亡率和高发病率的患者的破坏性后果有关。IA的形成仍然知之甚少。阐明特定的血流动力学在IA发生中的作用，将为从新的机制上理解IA的生长和可能的破裂铺平道路。

DESCRIPTION (provided by applicant): Little is known about intracranial aneurysm (IA) formation. We submit that specific hemodynamic conditions, not evaluated in prior aneurysm models, are critical for IA formation. Using a rabbit IA model, this project seeks to define these specific hemodynamic conditions responsible for aneurysm initiation and to identify key molecular responses in the pathological vascular remodeling that initiates aneurysms. We hypothesize that: 1) unusual hemodynamics at cerebrovascular bifurcations that is characterized by high wall shear stress (WSS) and wall shear stress gradient (WSSG) induces aneurysmal destructive remodeling, and 2) this pathological response is mediated by localized hemodynamic stimulation of nitric oxide (NO) production and matrix metalloproteinase (MMP) activity. We will evaluate the dose-dependence of this hemodynamic initiation of IAs and use computational fluid dynamics (CFD) to map the initiating hemodynamics. This will define the specific hemodynamic conditions responsible for inducing BT aneurysms, and allow subsequent experiments to examine the biological responses to IA-initiating hemodynamics that precede aneurysm formation. We will then examine hemodynamically induced changes in nitric oxide production and MMP activity during this early period of aneurysm initiation. The roles of NO and MMP in hemodynamic induction of IAs will be tested via pharmacological manipulation of these molecules. Aim 1. Determine specific hemodynamic conditions responsible for flow-induced IA initiation. Aim 2. Determine the role of MMPs in hemodynamic initiation of IAs. Aim 3. Determine the role of iNOS in regulating hemodynamic initiation of IAs. Significance: IA rupture is associated with devastating consequences for patients with high mortality and morbidity. IA formation remains poorly understood. Elucidating the role of specific hemodynamics in IA initiation will pave the way for new mechanistic understandings of IA growth and possibly rupture.