Abstract 5308: Role of Vascular Endothelial Growth Factor-A in the Development of Mice CaCl 2 Induced Abdominal Aortic Aneurysm

Abstract

Background: Abdominal aortic aneurysm (AAA) is histologically characterized by increased angiogenesis, chronic inflammation, and extracellular matrix degradation. We sought to elucidate the role of vascular endothelial growth factor (VEGF)-A, which is a potent angiogenic and proinflammatory factor, in the development of AAA. Methods and Results: We obtained human aortic wall samples (n=10) during surgical repair of AAA. Autopsy samples from normal aortic wall were served as control (n=6). Immunohistochemistry showed increased CD31 positive vessels, VEGF-A expression, and CD68 positive macrophage infiltration in the aortic wall of AAA compared with control samples. Next, we induced AAA in mice by periaortic application of CaCl 2 . Mice were treated with intraperitoneal injection of soluble VEGF-A receptor-1 (sFlt-1) 1mg/g (FLT, n=8) or PBS 1 μ l (CON, n=8) on alternative day and sacrificed 28 days after the operation. Blood pressure, heart rate, and body weight on day 28 were comparable between FLT and CON. Treatment with sFlt-1 significantly reduced aneurismal size (1.7±0.9 vs. 1.3±0.2 mm, p< 0.01) in association with lowering serum VEGF-A level (p< 0.01). Elastica von Gieson staining showed that wavy morphology of the elastic lamellae was destroyed in CON, but was preserved in FLT. Administration of sFlt-1 reduced zymographic active form of matrix metalloproteinase (MMP)-9 abundance and decreased MMP-9 positive cell count in the aortic wall compared with CON (both p<0.05). Immunohistochemistry showed significantly fewer Mac-3 positive monocytes/macrophages, CD31 and VEGF-A positive cells in periaortic tissues in FLT compared with CON (all p<0.05). Aortic wall mRNA expression of MCP-1, TNF-alpha, and TNF-alpha converting enzyme (TACE) in FLT was lower than that in CON (all p< 0.05). Immunoblotting showed decreased expression of p-JNK in FLT compared with CON (p< 0.05). Conclusions: VEGF-A was overexpressed in arterial wall of human AAA and experimental model of AAA. Treatment with sFlt-1 in mice prevented AAA development, in association with reduced neoangiogenesis, MMPs activity, infiltration of inflammatory cells and JNK activity, and preserved ECM structure. These findings suggest a crucial role of VEGF-A in the development of AAA.