Mechanisms and Significance of Angiogenesis in AAA Disease

项目总结/摘要 腹主动脉瘤（AAA）是美国成年人常见的致命疾病。进步 AAA扩大，在数月至数年的过程中，导致猝死的风险不断增加， 灾难性的破裂目前，破裂只能通过及时的手术修复来预防， 相当高的发病率和/或需要持续监测和定期再干预。之前 试图鉴定用于医疗干预的特定介体或途径靶点， 有效的临床治疗。虽然中膜和外膜新生血管形成（壁血管生成）良好， 尽管在人类和实验性AAA中已经认识到血管生成在AAA发病机制中的作用， 研究了根据我们的初步发现，VEGF-A产生细胞在血管平滑肌细胞中增加， 并且可溶性VEGFR-2或VEGFR抑制剂舒尼替尼对VEGF信号传导的抑制显著 抑制AAA的进展，我们的基本假设是VEGF-A介导的壁血管生成是 是主动脉瘤发病机制中的关键和限速因素，并且VEGF信号传导的操纵将 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 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VEGF-A的动力学和细胞起源 在动脉瘤发展过程中表达。我们将使用多种遗传工具来阻断VEGF-A， 系统性和细胞特异性的方式来定义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的进展和消退。阐明VEGF-A驱动的血管生成的发病学意义 在AAA疾病中的应用将促进新兴的抗血管生成治疗策略的快速转化， 有效的动脉瘤抑制的非手术方法。

Project Summary/Abstract 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.