Biphasic Effects of Statins on Angiogenesis-Mediated Processes.

Abstract

Background: Statins inhibit HMG-CoA reductase, resulting in the reduction of cholesterol synthesis as well as isoprenoids that modulate various cell functions.Methods: The present study was undertaken to determine the effects of different statins (lovastatin, fluvastatin, simvastatin, and pravastatin) on endothelial cell functions and angiogenesis. The effect of statins on endothelial cell migration toward matrix proteins and stimulated with tissue factor (TF)/factor VIIa was examined using modified Boyden chamber technique. Additionally, the effect of statins on endothelial differentiation and tube formation was determined in unstimulated and basic fibroblast growth factor (FGF-2) -stimulated endothelial cell tube formation. Furthermore, the effect of statins on the modulation of new blood vessel generation in the chick chorioallantoic membrane (CAM) model was determined under unstimulated and stimulated angiogenesis by FGF-2 or insulin.Results: Endothelial cell migration toward vitronectin and stimulated by TF/VIIa was shown to be inhibited by the various statins in a concentration (0.001–10 μM) -dependent manner. Endothelial cell differentiation and tube formation were enhanced by statins at low concentrations (0.01–0.001 μM) but inhibited at relatively high concentrations (0.1–10 μM) either in unstimulated or FGF-2-stimulated conditions, with different IC50s depending on the statin. In FGF-2- or insulin-stimulated angiogenesis in the CAM model, lovastatin demonstrated significant inhibition (40-75%) at 1–5 μg. In contrast, in unstimulated state lovastatin enhanced angiogenesis in the CAM model by 20–40% at 1–5 μg. Statins have proangiogenesis effects at low concentration in unstimulated or stimulated states but angiostatic effects at high concentrations in stimulated state. Similar biphasic effects on angiogenesis-mediated processes were determined with pravastatin, fluvastatin, or simvastatin, but with different potency. The antiangiogenesis efficacy was significantly (P <0.01) greater for the different statins in inhibiting insulin versus FGF-2-induced angiogenesis.Conclusion: Statins have a biphasic dose-dependent effect on angiogenesis-mediated processes that depend on the microenvironment and status of the proangiogenesis stimuli. At clinically relevant doses, statins may modulate angiogenesis depending on the proangiogenesis/antiangiogenesis hemostasis.Table 1. Modulation of Angiogenesis by Statins in the Chick Chorioallantoic Membrane ModelTreatmentNo. of Branch Points ± SEM% Inhibition ± SEMPBS (control)76 ± 10-----PBS + lovastatin (5 ug)120 ± 12-----FGF-2189 ± 13-----FGF-2 + lovastatin (5 ug)108 ± 865 ± 8FGF = fibroblast growth factor; PBS = phosphate-buffered saline.Table 2. Statins and Angiogenesis Modulation in the Chick Chorioallantoic Membrane ModelTreatmentBranch Points ± SEM% Inhibition ± SEMPBS (control)72 ± 8-----Insulin (1 ug)163 ± 12-----PBS + lovastatin (5 ug)119 ± 8-----PBS + pravastatin (5 ug)109 ± 11-----Insulin + lovastatin (5 ug)117 ± 950 ± 10Insulin + pravastatin (5 ug)113 ± 854 ± 9PBS = phosphate-buffered saline.