title: Statins have biphasic effects on angiogenesis.
abstract: BACKGROUND
  Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol and isoprenoids that modulate diverse cell functions. We investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis in vitro and in vivo.
  
  
  RESULTS
  Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 micromol/L) but significantly inhibited at high statin concentrations (0.05 to 1 micromol/L). Antiangiogenic effects at high concentrations were associated with decreased endothelial release of vascular endothelial growth factor and increased endothelial apoptosis and were reversed by geranylgeranyl pyrophosphate. In murine models, inflammation-induced angiogenesis was enhanced with low-dose statin therapy (0.5 mg x kg(-1) x d(-1)) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg x kg(-1) x d(-1)). Despite the fact that high-dose statin treatment was effective at reducing lipid levels in hyperlipidemic apolipoprotein E-deficient mice, it impaired rather than enhanced angiogenesis. Finally, high-dose cerivastatin decreased tumor growth and tumor vascularization in a murine Lewis lung cancer model.
  
  
  CONCLUSIONS
  HMG-CoA reductase inhibition has a biphasic dose-dependent effect on angiogenesis that is lipid independent and associated with alterations in endothelial apoptosis and vascular endothelial growth factor signaling. Statins have proangiogenic effects at low therapeutic concentrations but angiostatic effects at high concentrations that are reversed by geranylgeranyl pyrophosphate. At clinically relevant doses, statins may modulate angiogenesis in humans via effects on geranylated proteins.
authors.affiliation: Stanford University School of Medicine, Division of Cardiovascular Medicine, Stanford, Calif 94305, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Weis
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
authors.forename: Alec J
authors.initials: AJ
authors.lastname: Glassford
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000188:drug therapy / Q000235:genetics; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D017978:Receptors, Growth Factor / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D001057:Apolipoproteins E; D016228:Endothelial Growth Factors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008222:Lymphokines; D011106:Polyisoprenyl Phosphates; D011725:Pyridines; D011758:Pyrroles; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000069059:Atorvastatin; C086276:cerivastatin; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; C002963:geranylgeranyl pyrophosphate