Mechanisms and Significance of Angiogenesis in AAA Disease

描述(申请人提供)：腹主动脉瘤(AAA)是美国成年人的一种常见且致命的疾病。在几个月到几年的过程中，AAA的渐进性扩大会导致灾难性破裂导致猝死的风险不断增加。目前，破裂只能通过及时的手术修复来预防，这会带来相当大的发病率和/或需要持续监测和定期重新干预。先前试图确定用于医疗干预的特定介体或途径靶点，但并未转化为有效的临床治疗。尽管内侧和外膜新生血管形成(壁性血管生成)在人和实验性AAA中得到了很好的认识，但血管生成在AAA发病机制中的作用尚未被研究。根据我们的初步发现，在动脉瘤中，产生血管内皮生长因子-A的细胞增加，并且血管内皮生长因子受体-2或血管内皮生长因子受体抑制剂Sunitinib抑制血管内皮生长因子信号转导通路可显著抑制腹主动脉瘤的进展，我们的基本假设是血管内皮生长因子-A介导的壁上血管生成是主动脉瘤发病机制中的关键和限速因子，并且通过调控血管内皮生长因子信号通路调节实验性动脉瘤的进展和消退。为了实现这一假说，我们提出了以下具体目标：1.确定AAA疾病中主动脉血管内皮生长因子-A的细胞来源和产生的数量。2.明确血管内皮生长因子-A信号在AAA疾病进展中的作用。3.评价FDA批准的VEGFR抑制剂稳定或消退AAA的能力。利用已建立的人AAA病小鼠主动脉弹性蛋白酶灌注模型，我们将采用免疫染色、共聚焦成像和ELISA法分析血管内皮生长因子-A在动脉瘤形成过程中的表达动力学和细胞来源。我们将使用多种基因工具，以全身性和细胞特异性的方式阻断血管内皮生长因子-A，以明确血管生成在腹主动脉瘤发病机制中的作用。我们将进一步评估FDA批准的抗血管生成药物(舒尼替尼和索拉非尼)对AAA进展和消退的影响。确认血管内皮生长因子-A在AAA疾病中的致病意义将有助于将新出现的抗血管生成治疗策略迅速转化为有效的非手术方法抑制动脉瘤。 公共卫生相关性：腹主动脉瘤(AAA)是一种常见的、病态的、经常致命的疾病。在研究血管壁血管生成如何影响动脉瘤进展的过程中，我们希望发现新的治疗策略来限制早期AAA疾病的进展，并在此过程中改善数百万美国人的健康和福祉。

DESCRIPTION (provided by applicant): Abdominal aorta aneurysm (AAA) is a common and lethal disease of adult Americans. Progressive AAA enlargement, over the course of months to years, leads to ever-increasing risk of sudden death from catastrophic rupture. Currently, rupture can only be prevented by timely surgical repair, which carries considerable morbidity and/or requirements for ongoing surveillance and periodic re-intervention. Prior attempts to identify specific mediator or pathway targets for medical intervention have not translated to effective clinical therapies. Although medial and adventitial neovessel formation (mural angiogenesis) is well recognized in human and experimental AAA, the role of angiogenesis in AAA pathogenesis has not been studied. Based on our preliminary findings that VEGF-A-producing cells were increased in aneurysmal aortae, and that inhibition of VEGF signaling by either soluble VEGFR-2 or VEGFR inhibitor sunitinib significantly suppressed AAA progression, it is our fundamental hypothesis that VEGF-A-mediated mural angiogenesis is a critical and rate-limiting factor in aortic aneurysm pathogenesis, and that manipulation of VEGF signaling will modulate progression and regression of experimental aneurysms. To pursue this hypothesis, we propose the following Specific Aims: 1. Determine cellular origin and magnitude of aortic VEGF-A production in AAA disease. 2. Define the role of VEGF-A signaling in AAA disease progression. 3. Evaluate ability of FDA-approved VEGFR inhibitors to stabilize or regress AAA. Using the well-established mouse aortic elastase infusion model of human AAA disease, we will employ immunostaining, confocal imaging and ELISA assays to analyze the kinetics and cellular origins of VEGF-A expression during aneurysm development. We will use multiple genetic tools to block VEGF-A both in a systemic and cell-specific manner to define the role of VEGF-A-driven angiogenesis in AAA pathogenesis. We will further evaluate the effects of FDA-approved anti-angiogenesis drugs (sunitinib and sorafenib) on the progression and regression of AAA. Confirming the pathogenetic significance of VEGF-A-driven angiogenesis in AAA disease will facilitate the rapid translation of emerging anti-angiogenesis therapeutic strategies to effective non-surgical methods of aneurysm suppression. PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysm (AAA) is a common, morbid and frequently lethal disease. In the course of investigating how mural angiogenesis influences aneurysm progression, we hope to discover novel treatment strategies to limit progression of early AAA disease and, in the process, improve the health and well-being of millions of Americans.