Angiopoietin-1 Induces Migration of Monocytes in a Tie-2 and Integrin-Independent Manner

Abstract

Abstract-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. (Hypertension. 2010;56:477-483.)

Hydrogels With Integrin-Binding Angiopoietin-1–Derived Peptide, QHREDGS, for Treatment of Acute Myocardial Infarction

“…45 It has also been reported that Ang1-mediated effects on monocyte adhesion and chemotaxis are both Tie2 and integrin independent. 46 Hence, QHREDGS may bind and promote the survival of cardiomyocytes, cardiac fibroblasts, and endothelial cells through integrin-binding but may not affect monocyte/macrophage function, which would account for the absence of a significant inflammatory response.…”

Angiopoietin-1 Requires Oxidant Signaling through p47phox to Promote Endothelial Barrier Defense

“…Furthermore, the highly restricted expression of Angpt-1’s receptor, Tie2, to endothelium confers additional cellular specificity to the in vivo results. Nonetheless, Angpt-1 could have acted on putative non-Tie-2 receptors [43], and extra-endothelial effects of p47phox deletion could still have factored into the observed permeability results. [8,9].…”

PTK7 + Mononuclear Cells Express VEGFR2 and Contribute to Vascular Stabilization by Upregulating Angiopoietin-1

“…These observations indicate that the presence of PTK7 itself is responsible for ANG-1 secretion in mononuclear cells. As ANG-1 is a well-known mediator secreted by pericytes to recruit VECs and promote vascular stability, 12, 28 PTK7 + cells may stabilize vessel formation via ANG-1 secretion. Thus, we investigated the functional role of ANG-1 in PTK7 + cells.…”

“…28, 41–43 ANG-1 expression from BM cells appears to have a critical role in angiogenesis, pericyte recruitment, and vascular stabilization. 12, 28, 44 Our findings show that PTK7 + cells highly express ANG-1 and that the vascular stability of VECs is ANG-1 dependent (Figure 5), suggesting that PTK7 + CD11b + cells supply ANG-1 to the angiogenic area to promote vascularization at an early angiogenic time point.…”