HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells

Endothelial progenitor cells (EPCs) have been isolated from circulating mon onuclear cells in peripheral blood and shown to incorporate into foci of ne ovascularization, consistent with postnatal vasculogenesis. These circulati ng EPCs are derived from bone marrow and are mobilized endogenously in resp onse to tissue ischemia or exogenously by cytokine stimulation. We show her e, using a chemotaxis assay of bone marrow mononuclear cells in vitro and E PC culture assay of peripheral blood from simvastatin-treated animals in vi vo, that the HMG-CoA reductase inhibitor, simvastatin, augments the circula ting population of EPCs. Direct evidence that this increased pool of circul ating EPCs originates from bone marrow and may enhance neovascularization w as demonstrated in simvastatin-treated mice transplanted with bone marrow f rom transgenic donors expressing beta -galactosidase transcriptionally regu lated by the endothelial cell-specific Tie-2 promoter. The role of Akt sign aling in mediating effects of statin on EPCs is suggested by the observatio n that simvastatin rapidly activates Akt protein kinase in EPCs, enhancing proliferative and migratory activities and cell survival. Furthermore, domi nant negative Akt overexpression leads to functional blocking of EPC bioact ivity. These findings establish that augmented mobilization of bone marrow- derived EPCs through stimulation of the Akt signaling pathway constitutes a novel function for HMG-CoA reductase inhibitors.