Effects of atorvastatin on angiogenesis in hindlimb ischemia and endothelial progenitor cell formation in rats.
OBJECTIVE
To investigate the mechanisms underlying the pro-angiogenic effects of statin, the effects of atorvastatin were investigated on the expression of angiogenic factors in ischemic hindlimbs of rats. The function and number of endothelial progenitor cells (EPCs) were investigated in hypertensive rats.


METHODS
Hindlimb ischemia rats were administered 10 or 30 mg/kg/day atorvastatin orally for 2 weeks. Angiogenesis was evaluated by a laser Doppler and by Isolectin-B4 immunostaining. The expressions of VEGF, IL-8, angiopoietin (Ang)-1, Ang-2, eNOS, and hemoxidase (HO)-1 were evaluated by Western blotting and immunohistochemistry. Spontaneously hypertensive rats (SHR) were administered 10 mg/kg/day atorvastatin. EPC function was evaluated by colony formation and migration. The EPC number was evaluated by CD34-positive cells.


RESULTS
A lowdose of atorvastatin, but not a highdose, significantly increased regional blood flow. Atorvastatin significantly increased the expressions of VEGF, IL-8, Ang-1, Ang-2, eNOS, and HO-1 proteins in ischemic hindlimbs. Atorvastatin significantly increased the number and colony formation of EPCs and decreased oxidation in mononuclear cells from SHR.


CONCLUSIONS
Atorvastatin strongly induced angiogenesis with increases in angiogenic cytokines, HO-1 and EPC numbers. Statins are thus considered potertial agents for therapeutic angiogenesis.
Matsumura
Mitsuyasu
M
Department of Cardiovascular Surgery, Nihon University School of Medicine, Tokyo, Japan.
Fukuda
Noboru
N
Kobayashi
Naohiko
N
Umezawa
Hisaki
H
Takasaka
Ayako
A
Matsumoto
Taro
T
Yao
En-Hui
EH
Ueno
Takahiro
T
Negishi
Nanao
N
D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage / Q000494:pharmacology; D042501:Angiogenic Proteins / Q000032:analysis; D000818:Animals; D000069059:Atorvastatin; D002452:Cell Count; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
D043925:Angiogenesis Inducing Agents; D042501:Angiogenic Proteins; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin