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Simvastatin Stimulates Vascular Endothelial Growth Factor Production by Hypoxia-inducible Factor-1α Upregulation in Endothelial Cells

Objective: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor and plays an important pathophysiological role in the maintenance of tissue structure as well as regeneration after ischemic injury. Three-hydroxy-3methylglutaryl-CoA reductase inhibitors reduce vascular inflammation and induce angiogenesis. This study examined whether simvastatin stimulates VEGF expression in endothelial cells as well as the nature of its underlying mechanism. Methods and Results: Simvastatin induced mRNA expression and protein secretion of VEGF in endothelial cells that were reversed by pretreatment with mevalonate and geranylgeranylpyrophosphate but not by farnesylpyrophosphate. Adenovirus-mediated expression of the dominant-negative mutant of RhoA induced VEGF mRNA and protein. Simvastatin increased hypoxia-inducible factor-1α (HIF-1α) protein level without changing its mRNA expression. Inhibition of RhoA had similar effects to simvastatin on VEGF expression. Inhibition of RhoA caused the translocation of HIF-1α to the nuclear fraction. Depletion of HIF-1α by RNA interference blocked simvastatin-induced VEGF mRNA expression. Conclusions: Simvastatin stimulates VEGF expression by RhoA downregulation and HIF-1α upregulation in endothelial cells. These data indicate a novel role for RhoA as a negative regulator of HIF-1α.