Vascular endothelial growth factor secreted by replicating hepatocytes induces sinusoidal endothelial cell proliferation during regeneration after partial hepatectomy in rats.
BACKGROUND
The aim of this study was to investigate regulatory mechanisms of sinusoidal endothelial cell (SEC) proliferation after hepatectomy in rats.


METHODS
We investigated expressions of vascular endothelial cell growth factor (VEGF) and its receptors, flt-1 and KDR/flk-1, in regenerating liver after 70% hepatectomy. Proliferation of both hepatocytes and SECs was also monitored by evaluating the proliferating cell nuclear antigen (PCNA) labeling index. Furthermore, VEGF production by cultured hepatocytes isolated at different times after hepatectomy was measured in vitro.


RESULTS
The expression of VEGF mRNA was increased markedly between 48 and 72 h after hepatectomy, and thereafter decreasing gradually. The immunohistochemical staining revealed that expression of VEGF started to increase 24 h after hepatectomy, with a peak at 72 h, and the majority of the VEGF-positive cells were hepatocytes located in periportal areas. Meanwhile, expression of flt-1 and KDR/flk-1 was observed along the sinusoids even before hepatectomy, but was increased between 72 and 120 h. Furthermore, VEGF production by cultured hepatocytes isolated 72 h after hepatectomy was significantly increased. The PCNA labeling index of the SECs exhibited a delayed and slower regenerative response in comparison to the hepatocytes, reaching a peak at 72 h.


CONCLUSIONS
These data strongly suggest that VEGF secreted by proliferating hepatocytes may represent an important stimulator of SEC proliferation.
Shimizu
H
H
First Department of Surgery, School of Medicine, Chiba University, Japan.
Miyazaki
M
M
Wakabayashi
Y
Y
Mitsuhashi
N
N
Kato
A
A
Ito
H
H
Nakagawa
K
K
Yoshidome
H
H
Kataoka
M
M
Nakajima
N
N
D000818:Animals; D002455:Cell Division / Q000502:physiology; D016228:Endothelial Growth Factors / Q000097:blood / Q000235:genetics / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology*; D008222:Lymphokines / Q000097:blood / Q000235:genetics / Q000502:physiology*; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D016326:Extracellular Matrix Proteins; D008222:Lymphokines; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C501164:Flt1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1