Open AccessPravastatin‐induced proangiogenic effects depend upon extracellular FGF‐2
Author(s) -
Shiota Masayuki,
Hikita Yuko,
Kawamoto Yukiko,
Kusakabe Hiromi,
Tanaka Masako,
Izumi Yasukatsu,
Nakao Takafumi,
Miura Katsuyuki,
Funae Yoshihiko,
Iwao Hiroshi
Publication year - 2012
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2011.01494.x
Subject(s) - pravastatin , protein kinase b , mapk/erk pathway , angiogenesis , pi3k/akt/mtor pathway , endothelial stem cell , chemistry , human umbilical vein endothelial cell , fibroblast growth factor , microbiology and biotechnology , phosphorylation , cancer research , endocrinology , medicine , pharmacology , biology , signal transduction , biochemistry , receptor , cholesterol , in vitro
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.