Hemodynamic Induction of Pathologic Remodeling Leading to Intracranial Aneurysms

描述（由申请人提供）：对颅内动脉瘤（IA）形成知之甚少。我们认为，在先前的动脉瘤模型中未评价的特定血流动力学条件对IA形成至关重要。使用兔IA模型，该项目旨在定义这些特定的血流动力学条件，负责动脉瘤的启动，并确定关键的分子反应的病理血管重塑，启动动脉瘤。我们假设：1）以高的壁切应力（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诱导血管破坏性重构，和2）这种病理反应由局部血流动力学刺激一氧化氮（NO）产生和基质金属蛋白酶（MMP）活性介导。我们将评价IA的这种血流动力学启动的剂量依赖性，并使用计算流体动力学（CFD）绘制启动血流动力学。这将定义引起BT动脉瘤的特定血液动力学条件，并允许后续实验检查动脉瘤形成前IA引发血液动力学的生物学反应。然后，我们将研究在动脉瘤形成的早期，血流动力学引起的一氧化氮产生和MMP活性的变化。NO和MMP在IA的血流动力学诱导中的作用将通过这些分子的药理学操作进行测试。目标1。确定导致血流诱导IA启动的特定血流动力学条件。目标二。确定MMPs在IA血流动力学启动中的作用。目标3。确定iNOS在调节IA血流动力学起始中的作用。意义：IA破裂与高死亡率和发病率的患者的毁灭性后果相关。IA的形成仍然知之甚少。阐明特定血流动力学在IA启动中的作用将为IA生长和可能破裂的新机制理解铺平道路。

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.