Monocyte chemotactic protein 3 is a homing factor for circulating angiogenic cells

Abstract

Circulating angiogenic cells (CAC) participate in cardiac repair. CAC recruitment to the ischaemic heart is mainly induced by the chemokine (C-X-C motif) receptor 4 (CXCR4)/stromal-cell derived factor-1α axis. However, CAC mobilization is only partly prevented by CXCR4 blockade, indicating that other mechanisms are involved. Since the expression of monocyte chemotactic protein 3 (MCP3) is increased in ischaemic hearts, we hypothesized that it may participate in CAC mobilization. CAC were obtained from peripheral blood mononuclear cells of healthy volunteers. In vitro migration of CAC was concentration-dependently increased by recombinant MCP3 (one-fold increase, P= 0.001), and this effect was inhibited by antibodies neutralizing the chemokine (C-C motif) receptor 1 (CCR1). CCR1 expression at the surface of CAC was confirmed by flow cytometry. Conditioned medium from heparan sulfate-activated macrophages, which contained MCP3, induced the migration of CAC (one-fold increase, P= 0.01). This increase was partly inhibited by CCR1 antibodies. The migration of CAC was also stimulated by macrophage inflammatory protein 3β. This effect was blocked by CCR7 antibodies and was of lower magnitude than that of MCP3. MCP3 induced the formation of blood vessels in Matrigel plugs implanted in mice (1.5-fold increase, P< 0.001). This effect was abrogated by anti-CCR1 antibodies. This study shows that MCP3 stimulates the migration of CAC and angiogenesis, suggesting that MCP3 may be useful to improve cardiac repair.