Dual role of vascular endothelial growth factor in hepatic ischemia-reperfusion injury.
BACKGROUND
Vascular endothelial growth factor (VEGF), a major angiogenic factor, mediates a variety of disease conditions through promotion of angiogenesis. It also plays a critical role as a potent proinflammatory cytokine in a variety of physiologic and pathologic immune responses. In the present study, we evaluated the expression of VEGF in hepatic warm ischemia-reperfusion (I/R) injury and examined the effect of recombinant human (rh)VEGF administration in an established murine model.


METHODS
The expression of VEGF in the liver was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry during I/R injury using 70% partial hepatic ischemia model. The effect of rhVEGF administration on I/R injury was evaluated by measuring liver function and histology. In addition, local inducible nitric oxide synthase (iNOS) and endothelial NO synthase expressions were examined to address the underlying mechanisms.


RESULTS
The local expression of VEGF was significantly up-regulated at 2 hours after reperfusion after 60 minutes of ischemia compared with that in the naive liver. VEGF was expressed predominantly in CD11b+ cells infiltrating into the ischemic liver. The administration of rhVEGF had a significant protective effect on ischemic injury in the liver. This effect was associated with the up-regulation of iNOS expression in the rhVEGF-treated liver.


CONCLUSIONS
We demonstrate a dual role of VEGF in hepatic warm I/R injury. Although endogenous VEGF is expressed and functional to initiate hepatic I/R injury, exogenous rhVEGF has a beneficial effect on the ischemic liver. These data may provide new insights into the role of VEGF as well as pathophysiology of hepatic I/R injury.
Tsurui
Yoshikazu
Y
Department of Surgery, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
Sho
Masayuki
M
Kuzumoto
Yukiyasu
Y
Hamada
Kaoru
K
Akashi
Satoru
S
Kashizuka
Hisanori
H
Ikeda
Naoya
N
Nomi
Takeo
T
Mizuno
Takashi
T
Kanehiro
Hiromichi
H
Nakajima
Yoshiyuki
Y
D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008102:Liver Circulation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D019001:Nitric Oxide Synthase / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000494:pharmacology
D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D019001:Nitric Oxide Synthase