Statins differentially regulate vascular endothelial growth factor synthesis in endothelial and vascular smooth muscle cells.
OBJECTIVE
HMG-CoA reductase inhibitors (statins) can modulate the formation of new blood vessels, but the reports on their contribution to angiogenesis are contradictory. Therefore, we investigated whether the effect of statins is dependent either on the concentration of the drug or on the cell type.


RESULTS
Under basal conditions human vascular smooth muscle cells (HVSMC) and microvascular endothelial cells (HMEC-1) constitutively generate and release vascular endothelial growth factor (VEGF). In contrast, primary macrovascular endothelial cells (HUVEC) produce minute amounts of VEGF. Different statins (atorvastatin, simvastatin and lovastatin, 1-10 micromol/l) significantly reduced basal and cytokine-, nitric oxide- or lysophosphatidylcholine (LPC)-induced VEGF synthesis in HMEC-1 and HVSMC. Interestingly, at the same concentrations statins upregulated VEGF generation in HUVEC. Furthermore, statins exerted dual, concentration-dependent influence on angiogenic activities of HUVEC as determined by tube formation assay. At low concentrations (0.03-1 micromol/l) the pro-angiogenic activity of statins is prevalent, whereas at higher concentrations statins inhibit angiogenesis, despite increasing VEGF synthesis.


CONCLUSIONS
Our data show that statins exert concentration- and cell type-dependent effects on angiogenic activity of endothelial cells and on VEGF synthesis. The data are of relevance for elucidating the differential activity of statins on angiogenesis in cardiovascular diseases and cancer.
Frick
Matthias
M
Division of Cardiology, Department of Medicine, Innsbruck University, Innsbruck, Austria.
Dulak
Jozef
J
Cisowski
Jarosław
J
Józkowicz
Alicja
A
Zwick
Ralf
R
Alber
Hannes
H
Dichtl
Wolfgang
W
Schwarzacher
Severin P
SP
Pachinger
Otmar
O
Weidinger
Franz
F
D000069059:Atorvastatin; D002478:Cells, Cultured; D003331:Coronary Vessels; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin