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

J Clin Invest. 2001 Aug;108(3):399-405. doi: 10.1172/JCI13131.

Abstract

Endothelial progenitor cells (EPCs) have been isolated from circulating mononuclear cells in peripheral blood and shown to incorporate into foci of neovascularization, consistent with postnatal vasculogenesis. These circulating EPCs are derived from bone marrow and are mobilized endogenously in response to tissue ischemia or exogenously by cytokine stimulation. We show here, using a chemotaxis assay of bone marrow mononuclear cells in vitro and EPC culture assay of peripheral blood from simvastatin-treated animals in vivo, that the HMG-CoA reductase inhibitor, simvastatin, augments the circulating population of EPCs. Direct evidence that this increased pool of circulating EPCs originates from bone marrow and may enhance neovascularization was demonstrated in simvastatin-treated mice transplanted with bone marrow from transgenic donors expressing beta-galactosidase transcriptionally regulated by the endothelial cell-specific Tie-2 promoter. The role of Akt signaling in mediating effects of statin on EPCs is suggested by the observation that simvastatin rapidly activates Akt protein kinase in EPCs, enhancing proliferative and migratory activities and cell survival. Furthermore, dominant negative Akt overexpression leads to functional blocking of EPC bioactivity. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chemotaxis / drug effects
  • Cornea / blood supply
  • Cornea / drug effects
  • Endothelial Growth Factors / pharmacology
  • Endothelium, Vascular / cytology*
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / drug effects*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • In Vitro Techniques
  • Lymphokines / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neovascularization, Physiologic / drug effects
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction / drug effects
  • Simvastatin / pharmacology
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lymphokines
  • Proto-Oncogene Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Simvastatin
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt