Intracranial Aneurysm Pathogenesis-Roles of Vascular Remodeling and Inflammation

描述(申请人提供)：由血液动力学应力引起的血管异常重塑被认为是颅内动脉瘤发生和破裂的关键过程之一。然而，血流动力学压力与颅内动脉瘤的发生和破裂之间的联系机制还不是很清楚。炎症细胞正在成为血管生成和血管重塑的关键介质。我们的一般假设是：(1)炎症细胞是血流诱导的外向血管重构的关键媒介；(2)颅内动脉瘤是一种异常重构的模型，它是由炎症细胞介导的过度血流动力学诱导的血管重构所致。目的1.中性粒细胞和巨噬细胞在血流诱导的适应性外向血管重塑中的关键作用。使用啮齿类动物颈总动脉血流增加模型，我们将证明中性粒细胞和/或巨噬细胞的耗竭减少了血流诱导的外向血管重构和血管壁中的基质金属蛋白酶(MMPs)。目的2.MMPs在血流诱导适应性外向血管重塑中的关键作用。我们将通过结合骨髓移植的药理学和遗传学方法，展示基质金属蛋白酶-9和基质金属蛋白酶-2在正常血流诱导的重塑中的关键作用。目的3.炎症细胞和基质金属蛋白酶在颅内动脉瘤形成中的关键作用--长期血流诱导的不良适应血管重塑。使用啮齿动物动脉瘤模型，我们将证明中性粒细胞和/或巨噬细胞的耗尽降低了颅内动脉瘤的发生率，并且与野生型小鼠相比，基质金属蛋白酶-9和基质金属蛋白酶-2基因敲除小鼠的动脉瘤形成发生率降低。关联性。阐明炎症细胞在正常血管重塑和异常血管重塑--颅内动脉瘤形成中的作用，将为未来研究开发新的治疗靶点以减缓或防止动脉瘤的生长和破裂奠定基础。未破裂的颅内动脉瘤的治疗仍然存在争议。在一些患者中，手术治疗的风险可能高于破裂的风险。通过抑制MMPs或其他细胞因子来针对血管重塑和炎症的新疗法可能会使这一亚群患者受益。

DESCRIPTION (provided by applicant): Abnormal vascular remodeling triggered by hemodynamic stresses on blood vessels is believed to be one of the key processes in the development and rupture of intracranial aneurysms. However, mechanisms linking hemodynamic stresses to the development and rupture of intracranial aneurysms are not well understood. Inflammatory cells are emerging as a key mediator for angiogenesis and vascular remodeling. Our general hypotheses are (1) inflammatory cells are key mediators for flow-induced outward vascular remodeling and (2) intracranial aneurysms, a model of abnormal remodeling, result from excessive hemodynamically- induced vascular remodeling mediated by inflammatory cells. Aim 1. Critical roles of neutrophils and macrophages in flow-induced adaptive outward vascular remodeling. Using a rodent common carotid artery flow augmentation model, we will demonstrate that depletion of neutrophils and/or macrophages reduces flow-induced outward vascular remodeling and matrix metalloproteinases (MMPs) in the vascular wall. Aim 2. Critical roles of MMPs in flow-induced adaptive outward vascular remodeling. We will demonstrate critical roles of MMP-9 and MMP-2 in normal flow- induced remodeling using pharmacological and genetic approaches coupled with bone marrow transplant. Aim 3. Critical roles of inflammatory cells and MMPs in intracranial aneurysm formation -long-term flow- induced maladaptive vascular remodeling. Using a rodent aneurysm model, we will demonstrate that depletion of neutrophils and/or macrophages decreases the incidence of intracranial aneurysms and that MMP-9 and MMP-2 knockout mice demonstrate reduced incidence of aneurysm formation compared to the wild type mice. Relevance. Elucidating the roles of inflammatory cells in normal vascular remodeling and abnormal vascular remodeling-intracranial aneurysm formation- will be the basis for future studies to develop new therapeutic targets to slow or prevent aneurysmal growth and rupture. The management of unruptured intracranial aneurysms still remains controversial. In some patients, the risks of surgical treatment may be higher than a risk of rupture. New treatments targeting vascular remodeling and inflammation through inhibition of MMPs or other cytokines could potentially benefit this subset of patients.