Double-edged role of statins in angiogenesis signaling.
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) exert potent vasculoprotective effects. However, the potential contribution to angiogenesis is controversial. In the present study, we demonstrate that atorvastatin dose-dependently affects endothelial cell migration and angiogenesis. In vivo relevant concentrations of 0.01 to 0.1 micromol/L atorvastatin or mevastatin promote the migration of mature endothelial cells and tube formation. Moreover, atorvastatin also increases migration and the potency to form vessel structures of circulating endothelial progenitor cells, which may contribute to vasculogenesis. In contrast, higher concentrations (>0.1 micromol/L atorvastatin) block angiogenesis and migration by inducing endothelial cell apoptosis. The dose-dependent promigratory and proangiogenic effects of atorvastatin on mature endothelial cells are correlated with the activation of the phosphatidylinositol 3-kinase-Akt pathway, as determined by the phosphorylation of Akt and endothelial NO synthase (eNOS) at Ser1177. In addition, the stimulation of migration and tube formation was blocked by phosphatidylinositol 3-kinase inhibitors. In contrast, the well-established stabilization of eNOS mRNA was achieved only at higher concentrations, suggesting that posttranscriptional activation rather than an increase in eNOS expression mediates the proangiogenic effect of atorvastatin. Taken together, these data suggest that statins exert a double-edged role in angiogenesis signaling by promoting the migration of mature endothelial cells and endothelial progenitor cells at low concentrations, whereas the antiangiogenic effects were achieved only at high concentrations.
Urbich
Carmen
C
Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany.
Dernbach
Elisabeth
E
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D001426:Bacterial Proteins; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D004768:Enterotoxins / Q000378:metabolism; D005347:Fibroblasts; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D001426:Bacterial Proteins; D004768:Enterotoxins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; C082174:cytolytic enterotoxin protein, Aeromonas; D000069059:Atorvastatin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases