Statins Have Biphasic Effects on Angiogenesis

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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. Methods and Results — Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 μmol/L) but significantly inhibited at high statin concentrations (0.05 to 1 μmol/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 · kg −1 · d −1 ) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg · kg −1 · 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.