Mechanisms and Significance of Angiogenesis in AAA Disease

描述（由申请人提供）：腹主动脉瘤（AAA）是美国成年人常见的致命疾病。在数月至数年的过程中，AAA进行性扩大导致灾难性破裂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，这带来了相当大的发病率和/或需要持续监测和定期再干预。先前尝试鉴定用于医学干预的特定介质或途径靶标尚未转化为有效的临床疗法。尽管在人类和实验性AAA中，中膜和外膜新生血管形成（壁血管生成）得到了广泛认可，但尚未研究血管生成在AAA发病机制中的作用。基于我们的初步发现，即VEGF-A产生细胞在腹主动脉瘤中增加，并且可溶性VEGFR-2或VEGFR抑制剂舒尼替尼抑制VEGF信号传导显著抑制AAA进展，我们的基本假设是VEGF-A介导的壁血管生成是主动脉瘤发病机制中的关键和限速因素，并且VEGF信号的操纵将调节实验性动脉瘤的进展和消退。为了实现这一假设，我们提出了以下具体目标：1。确定AAA疾病中主动脉VEGF-A产生的细胞来源和幅度。2.明确VEGF-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。 使用完善的人AAA疾病的小鼠主动脉弹性蛋白酶输注模型，我们将采用免疫染色，共聚焦成像和ELISA测定来分析动脉瘤发展过程中VEGF-A表达的动力学和细胞起源。我们将使用多种遗传工具以系统和细胞特异性方式阻断VEGF-A，以确定VEGF-A驱动的血管生成在AAA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。阐明VEGF-A驱动的血管生成在AAA疾病中的发病学意义将有助于将新兴的抗血管生成治疗策略快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、病态的和经常致命的疾病。在研究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.