Gustav Born Centre for Vascular Biology, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Hypertension. 2010 Sep;56(3):477-83. doi: 10.1161/HYPERTENSIONAHA.110.155556. Epub 2010 Aug 9.
Angiopoietin-1 (Ang-1) is an angiogenic growth factor that activates Tie-2 and integrins to promote vessel wall remodeling. The recent finding of the potential proatherogenic effects of Ang-1 prompted us to investigate whether Ang-1 promotes monocyte chemotaxis, endothelial binding, and transendothelial migration, key events in the progression of atherosclerosis. Here, we show that Ang-1 induces chemotaxis of monocytes in a manner that is independent of Tie-2 and integrin binding but dependent on phosphoinositide 3-kinase and heparin. In addition, Ang-1 promoted phosphoinositide 3-kinase-dependent binding of monocytes to endothelial monolayers and stimulated transendothelial migration. Fluorescence-activated cell sorting analysis showed that exogenous Ang-1 adheres directly to monocytes as well as to human umbilical endothelial cells, but neither Tie-2 mRNA nor protein were expressed by primary monocytes. Although Ang-1 binding to human umbilical endothelial cells was partially Tie-2 and integrin dependent, Ang-1 binding to monocytes was independent of these factors. Finally, preincubation of monocytes with soluble heparin abrogated Ang-1 binding to monocytes and migration, and partially prevented Ang-1 binding to human umbilical endothelial cells. In summary, Ang-1 induces chemotaxis of monocytes by a mechanism that is dependent on phosphoinositide 3-kinase and heparin but independent of Tie-2 and integrins. The ability of Ang-1 to recruit monocytes suggests it may play a role in inflammatory angiogenesis and may promote atherosclerosis.
血管生成素-1（Ang-1）是一种血管生成生长因子，它可以激活 Tie-2 和整合素，促进血管壁重塑。最近发现 Ang-1 具有潜在的促动脉粥样硬化作用，这促使我们研究 Ang-1 是否促进单核细胞趋化、内皮细胞结合和跨内皮迁移，这些都是动脉粥样硬化进展的关键事件。在这里，我们表明 Ang-1 以一种独立于 Tie-2 和整合素结合但依赖于磷酸肌醇 3-激酶和肝素的方式诱导单核细胞趋化。此外，Ang-1 促进了单核细胞与内皮单层的磷酸肌醇 3-激酶依赖性结合，并刺激了跨内皮迁移。荧光激活细胞分选分析表明，外源性 Ang-1 直接粘附于单核细胞和人脐静脉内皮细胞，但原代单核细胞既不表达 Tie-2 mRNA 也不表达 Tie-2 蛋白。尽管 Ang-1 与人脐内皮细胞的结合部分依赖于 Tie-2 和整合素，但 Ang-1 与单核细胞的结合不受这些因素的影响。最后，单核细胞预先用可溶性肝素孵育可阻断 Ang-1 与单核细胞的结合和迁移，并部分阻止 Ang-1 与人脐内皮细胞的结合。总之，Ang-1 通过一种依赖于磷酸肌醇 3-激酶和肝素但不依赖于 Tie-2 和整合素的机制诱导单核细胞趋化。Ang-1 招募单核细胞的能力表明它可能在炎症性血管生成中发挥作用，并可能促进动脉粥样硬化。
