Mechanisms and Significance of Angiogenesis in AAA Disease

项目摘要/摘要 腹主动脉瘤(AAA)是美国成年人的常见致命性疾病。渐进式 AAA的扩大，在几个月到几年的过程中，会导致因以下原因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外科修复来预防，这意味着 相当高的发病率和/或持续监测和定期再干预的要求。之前 试图确定用于医疗干预的特定介体或途径靶点并未转化为 有效的临床疗法。尽管内侧和外膜新生血管形成(壁性血管生成)良好 在人类和实验性AAA中，血管生成在AAA发病机制中的作用尚不清楚。 学习。根据我们的初步发现，动脉瘤中产生血管内皮生长因子-A的细胞增加， 可溶性VEGFR-2或VEGFR抑制剂Sunitinib显著抑制血管内皮生长因子信号转导 抑制AAA进展，这是我们的基本假设，即血管内皮生长因子-A介导的壁上血管生成是 在主动脉瘤发病机制中的关键和限速因素，以及对血管内皮生长因子信号的操作将 调节实验性动脉瘤的进展和消退。为了进一步研究这一假设，我们提出了 以下是具体目标： 1.确定腹主动脉疾病中血管内皮生长因子-A的细胞来源和表达的大小。 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。 使用已建立的人类AAA疾病的小鼠主动脉弹性蛋白酶输注模型，我们将使用 免疫染色、共聚焦成像和ELISA法分析血管内皮生长因子-A的动力学和细胞来源 在动脉瘤形成过程中的表达。我们将使用多种基因工具来阻断血管内皮生长因子-A 以系统和细胞特异性的方式确定血管内皮生长因子-A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)对血管生成的影响 腹主动脉瘤的进展和消退。确认血管内皮生长因子-A在血管生成中的病理意义 将促进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。

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.