Abstract 5308: Role of Vascular Endothelial Growth Factor-A in the Development of Mice CaCl2 Induced Abdominal Aortic Aneurysm
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 CaCl2. Mice were treated with intraperitoneal injection of soluble VEGF-A receptor-1 (sFlt-1) 1mg/g (FLT, n=8) or PBS 1μl (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.