Abstract 810: Recruitment of the Inflammatory Subset of Monocytes to Sites of Ischemia Induces Angiogenesis in a Monocyte Chemoattractant Protein-1 Dependent Fashion
Our lab has previously shown that mobilization of monocytes from the bone marrow to the blood by G-CSF and/or AMD3100 administration stimulated angiogenesis and enhanced revascularization following the induction of hindlimb ischemia in mice. Recent data suggest that monocytes can be divided into two distinct subsets based upon the expression of the fractalkine receptor CX3CR1. The inflammatory subset of monocytes express low levels of CX3CR1 but high levels of CCR2 and Gr-1. In contrast, the resident subset of monocytes express high levels of CX3CR1 but no CCR2 or Gr-1. Using transgenic mice expressing GFP under the control of the 2.1kb CX3CR1 promoter, we sorted inflammatory and resident monocytes and adoptively transferred them into mice 24 hours after the induction of hindlimb ischemia. Whereas inflammatory monocytes markedly improved revascularization, no effect was observed with resident monocytes. These data suggest that the inflammatory monocyte subset may be an attractive cell population to study in the therapeutic setting. The mechanism by which monocytes stimulate angiogenesis at sites of inflammation is not fully understood. Herein, we show that adoptively transferred CFSE-labeled monocytes are rapidly and specifically recruited from the blood to the ischemic hindlimb. These recruited donor monocytes induce a massive secondary recruitment of host monocytes that is associated with local production of MCP-1. To further explore the role of MCP-1 in this process, we repeated these adoptive transfer experiments in MCP-1−/ − mice. Adoptive transfer of wild type monocytes into wild type mice markedly improved revascularization while no angiogenic effect was observed after adoptive transfer into MCP-1−/ − mice. Moreover, whereas recruitment of adoptively transferred CFSE-labeled monocytes into the ischemic limb in MCP-1−/ − mice was normal, the induction of MCP-1 expression and secondary recruitment of endogenous monocytes from the blood was significantly attenuated. Furthermore, MCP-1−/ − mice showed no enhancement of angiogenesis following mobilization with G-CSF and AMD3100. These data suggest that MCP-1 plays a key role in the inflammatory angiogenic response by recruiting host monocytes from the blood into the ischemic tissue.