Simultaneous transfer of vascular endothelial growth factor and hepatocyte growth factor genes effectively promotes liver regeneration after hepatectomy in cirrhotic rats.
OBJECTIVE
Liver regeneration in a cirrhotic liver is unsatisfactory. In the course of liver regeneration, non-parenchymal cells such as sinusoidal endothelial cells as well as hepatocytes increase in number while the liver structure and physiological functions are maintained. The aim of this study was to examine whether sufficient liver regeneration could be obtained by the simultaneous, preoperative injection of recombinant adenoviral vectors encoding human vascular endothelial growth factor (VEGF), a potent mitogen for sinusoidal endothelial cells, (pAxCAVEGF) and rat hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, (pAxCAHGF) in 70% hepatectomized cirrhotic rats.


METHODS
Forty-eight hours before 70% hepatectomy, dimethylnitrosamine-induced cirrhotic rats were infused intravenously with pAxCAVEGF or with pAxCAVEGF and pAxCAHGF, or with a control virus encoding Escherichia coli beta-galactosidase (pAxCALacZ).


RESULTS
Strong VEGF mRNA expressions were shown in the livers of VEGF and VEGF/HGF-treated animals. The plasma HGF concentrations in the VEGF/HGF-treated rats were elevated compared with the other groups. Proliferating cell nuclear antigen immunostaining showed increased labeling indices of hepatocytes in the VEGF/HGF-treated rats at 24 and 48 h after hepatectomy. PCNA labeling indices of SECs were increased in the VEGF and VEGF/HGF-treated rats compared with the control animals at 24 and 48 h after hepatectomy. Moreover, the hepatic regeneration rate after hepatectomy was significantly augmented by the VEGF and VEGF/HGF treatment.


CONCLUSIONS
Simultaneous preoperative injection of recombinant adenoviral vectors encoding VEGF and HGF effectively stimulates liver regeneration in cirrhotic rats.
Oe
Hideaki
H
Department of Surgery and Surgical Basic Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kaido
Toshimi
T
Furuyama
Hiroaki
H
Mori
Akira
A
Imamura
Masayuki
M
D000818:Animals; D001707:Biopsy, Needle; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D007150:Immunohistochemistry; D008106:Liver Cirrhosis, Experimental / Q000628:therapy*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D011300:Preoperative Care; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012680:Sensitivity and Specificity; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor