Fujisawa Takeshi, Wang Keqing, Niu Xi-Lin, Egginton Stuart, Ahmad Shakil, Hewett Peter, Kontos Christopher D, Ahmed Asif
Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, U.K.
Gustav Born Centre for Vascular Biology and BHF Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Cardiovasc Res. 2017 Jan;113(1):81-89. doi: 10.1093/cvr/cvw223.
Atherosclerosis is a chronic inflammatory disease occurring within the artery wall. A crucial step in atherogenesis is the infiltration and retention of monocytes into the subendothelial space of large arteries induced by chemokines and growth factors. Angiopoietin-1 (Ang-1) regulates angiogenesis and reduces vascular permeability and has also been reported to promote monocyte migration in vitro. We investigated the role of Ang-1 in atherosclerosis-prone apolipoprotein-E (Apo-E) knockout mouse.
Apo-E knockout (Apo-E) mice fed a western or normal chow diet received a single iv injection of adenovirus encoding Ang-1 or control vector. Adenovirus-mediated systemic expression of Ang-1 induced a significant increase in early atherosclerotic lesion size and monocyte/macrophage accumulation compared with control animals receiving empty vector. Ang-1 significantly increased plasma MCP-1 and VEGF levels as measured by ELISA. FACS analysis showed that Ang-1 selectively increased inflammatory Gr1monocytes in the circulation, while the cell-surface expression of CD11b, which mediates monocyte emigration, was significantly reduced.
Ang-1 specifically increases circulating Gr1inflammatory monocytes and increases monocyte/macrophage retention in atherosclerotic plaques, thereby contributing to development of atherosclerosis.
动脉粥样硬化是一种发生在动脉壁内的慢性炎症性疾病。动脉粥样硬化形成过程中的一个关键步骤是趋化因子和生长因子诱导单核细胞浸润并滞留在大动脉的内皮下间隙。血管生成素-1（Ang-1）调节血管生成并降低血管通透性，也有报道称其在体外可促进单核细胞迁移。我们研究了Ang-1在易患动脉粥样硬化的载脂蛋白E（Apo-E）基因敲除小鼠中的作用。
喂食西式或正常饲料的Apo-E基因敲除（Apo-E）小鼠接受单次静脉注射编码Ang-1的腺病毒或对照载体。与接受空载体的对照动物相比，腺病毒介导的Ang-1全身表达导致早期动脉粥样硬化病变大小和单核细胞/巨噬细胞积聚显著增加。通过酶联免疫吸附测定法测得，Ang-1显著提高血浆MCP-1和VEGF水平。流式细胞术分析显示，Ang-1选择性增加循环中炎性Gr1单核细胞，而介导单核细胞迁出的细胞表面分子CD11b的表达显著降低。
Ang-1特异性增加循环中的Gr1炎性单核细胞，并增加单核细胞/巨噬细胞在动脉粥样硬化斑块中的滞留，从而促进动脉粥样硬化的发展。
