Intracranial Aneurysm Pathogenesis-Roles of Vascular Remodeling and Inflammation

描述（由申请人提供）：血管上的血流动力学应力触发的异常血管重塑被认为是颅内动脉瘤发展和破裂的关键过程之一。然而，血流动力学应力与颅内动脉瘤的发展和破裂之间的联系机制尚不清楚。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塑的关键介质，（2）颅内动脉瘤（一种异常重塑模型）是由炎症细胞介导的过度血流动力学诱导的血管重塑引起的。目标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强模型，我们将证明，中性粒细胞和/或巨噬细胞的耗竭减少流动诱导的外向血管重塑和血管壁中的基质金属蛋白酶（MMPs）。目标二。基质金属蛋白酶在血流诱导的适应性外向血管重塑中的关键作用。我们将使用药理学和遗传学方法结合骨髓移植来证明MMP-9和MMP-2在正常血流诱导的重塑中的关键作用。目标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-长期血流诱导的适应不良血管重塑。使用啮齿动物动脉瘤模型，我们将证明中性粒细胞和/或巨噬细胞的耗竭降低颅内动脉瘤的发生率，并且MMP-9和MMP-2敲除小鼠与野生型小鼠相比显示动脉瘤形成的发生率降低。本案无关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是未来研究开发新的治疗靶点以减缓或预防动脉瘤生长和破裂的基础。未破裂颅内动脉瘤的治疗仍存在争议。在某些患者中，手术治疗的风险可能高于破裂的风险。通过抑制MMPs或其他细胞因子靶向血管重塑和炎症的新疗法可能使这部分患者受益。

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.