Recruitment of the inflammatory subset of monocytes to sites of ischemia induces angiogenesis in a monocyte chemoattractant protein-1-dependent fashion

Abstract

There is accumulating evidence that delivery of bone marrow cells to sites of ischemia by direct local injection or mobilization into the blood can stimulate angiogenesis. This has stimulated tremendous interest in the translational potential of angiogenic cell population(s) in the bone marrow to mediate therapeutic angiogenesis. However, the mechanisms by which these cells stimulate angiogenesis are unclear. Herein, we show that the inflammatory subset of monocytes is selectively mobilized into blood after surgical induction of hindlimb ischemia in mice and is selectively recruited to ischemic muscle. Adoptive-transfer studies show that delivery of a small number of inflammatory monocytes early (within 48 h) of induction of ischemia results in a marked increase in the local production of MCP-1, which in turn, is associated with a secondary, more robust wave of monocyte recruitment. Studies of mice genetically deficient in MCP-1 or CCR2 indicate that although not required for the early recruitment of monocytes, the secondary wave of monocyte recruitment and subsequent stimulation of angiogenesis are dependent on CCR2 signaling. Collectively, these data suggest a novel role for MCP-1 in the inflammatory, angiogenic response to ischemia.

Multiple roles for CCR2 during fracture healing

“…We found that, compared with wild-type animals, the vasculature within fracture callus in Ccr2-/-mice had a reduced surface area for nutrient exchange. This observation is consistent with other reports demonstrating that impaired macrophage recruitment in Ccr2-/-mice leads to a reduction in tissue vascular endothelial growth factor (VEGF) levels and a delay in capillary formation (Capoccia et al, 2008;Ochoa et al, 2007). Macrophages are key effectors of angiogenesis that contribute to tumor angiogenesis in several carcinomas (Mazibrada et al, 2008;Ohta et al, 2002), and tumor-associated macrophages have been shown to express VEGF (Gonzalez et al, 2007).…”

Truncation of monocyte chemoattractant protein 1 by plasmin promotes blood–brain barrier disruption

“…By binding to their specific Gprotein-coupled receptors, chemokines induce cell-specific migration and activation of immune cells (Glabinski et al, 1996;Hulkower et al, 1993;Lahrtz et al, 1998;Miller and Meucci, 1999). Monocyte chemoattractant protein-1 (MCP1; officially known as C-C motif chemokine 2, CCL2) is one of the most highly and transiently expressed chemokines in many central nervous system (CNS) injuries, including ischemia, hemorrhage and excitotoxic injury (Capoccia et al, 2008;Dimitrijevic et al, 2006;Frangogiannis et al, 2007;Hanisch, 2002;Kim et al, 2008;Morimoto et al, 2008;Sheehan et al, 2007;Yan et al, 2007). The rodent MCP1 differs from the human protein at the C-terminus, with the rodent protein having a longer highly glycosylated Cterminus.…”

Pulmonary Hypertension Associated With HIV Infection

“…37 Also, Nef is a migratory stimulus for monocytes 38 and induces the release of infl ammatory molecules. 39 Capoccia and colleagues 40 proposed a model in which Nef induces early recruitment of infl ammatory monocytes, which in turn induce a secondary wave of monocytes followed by angiogenesis.…”