Angiopoietin-1 induces migration of monocytes in a tie-2 and integrin-independent manner.
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.
Ahmad
Shakil
S
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.
Cudmore
Melissa J
MJ
Wang
Keqing
K
Hewett
Peter
P
Potluri
Rahul
R
Fujisawa
Takeshi
T
Ahmed
Asif
A
D042683:Angiopoietin-1 / Q000378:metabolism / Q000494:pharmacology*; D042702:Angiopoietin-2 / Q000378:metabolism / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism*
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D016023:Integrins; D006493:Heparin; D019869:Phosphatidylinositol 3-Kinases; D042787:Receptor, TIE-2