title: Pravastatin-induced proangiogenic effects depend upon extracellular FGF-2.
abstract: The HMG-CoA reductase inhibitors (statins) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile, and to induce angiogenesis. The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K/Akt pathway in endothelial cells; however, it is unclear how statins activate this pathway. Pravastatin-mediated activation of Akt and MAPK occurs rapidly (within 10 min.) and at low doses (10 nM). Here, we hypothesized that FGF-2 contributes to the proangiogenic effect of statins. We found that pravastatin, a hydrophilic statin, induced phosphorylation of the FGF receptor (FGFR) in human umbilical vein endothelial cells. SU5402, an inhibitor of FGFR, abolished pravastatin-induced PI3K/Akt and MAPK activity. Likewise, anti-FGF-2 function-blocking antibodies inhibited Akt and MAPK activity. Moreover, depletion of extracellular FGF-2 by heparin prevented pravastatin-induced phosphorylation of Akt and MAPK. Treatment with FGF-2 antibody inhibited pravastatin-enhanced endothelial cell proliferation, migration and tube formation. These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular FGF-2.
authors: Department of Pharmacology, Osaka City University Medical School, Osaka, Japan. sio@med.osaka-cu.ac.jp
authors: Masayuki
authors: M
authors: Shiota
authors: Yuko
authors: Y
authors: Hikita
authors: Yukiko
authors: Y
authors: Kawamoto
authors: Hiromi
authors: H
authors: Kusakabe
authors: Masako
authors: M
authors: Tanaka
authors: Yasukatsu
authors: Y
authors: Izumi
authors: Takafumi
authors: T
authors: Nakao
authors: Katsuyuki
authors: K
authors: Miura
authors: Yoshihiko
authors: Y
authors: Funae
authors: Hiroshi
authors: H
authors: Iwao
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017035:Pravastatin / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D016222:Fibroblast Growth Factor 2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017035:Pravastatin; D051057:Proto-Oncogene Proteins c-akt; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; C105686:SU 5402