Effect of vascular endothelial growth factor on functional recovery after hepatectomy in lean and obese mice.
OBJECTIVE
Liver regeneration is dependent upon coordinated proliferation of hepatocytes and endothelial cells. Vascular endothelial growth factor (VEGF) promotes angiogenesis. Hepatic steatosis delays regeneration and increases liver resection morbidity. We hypothesized that VEGF overexpression stimulates hepatic regeneration.


METHODS
Recombinant adenovirus expressing human VEGF165 or adenovirus control-vector (LacZ) were administered before 2/3 hepatectomy in lean and ob/ob mice. Galactose elimination capacity, a quantitative liver function test, was repeatedly measured before and after hepatectomy. Expression of VEGF receptors (flt1, flk1), endoglin and hypoxia inducible factor-1alpha (HIF-1alpha) was assessed by quantitative RT-PCR and for endoglin also by immunohistochemistry.


RESULTS
After 2/3 hepatectomy, VEGF gene transfer increased galactose elimination capacity in lean and ob/ob mice. HIF-1alpha, endoglin and VEGF receptor mRNA increased during regeneration in lean but not in obese mice. Staining of endothelial cells by endoglin immunohistochemistry returned to baseline reactivity in lean mice by day 6 and remained decreased in ob/ob mice. VEGF treatment decreased HIF-1alpha and increased flk1 response in lean mice.


CONCLUSIONS
Hepatic resection elicits an angiogenic response in the remnant liver, which is impaired in case of steatosis. Adenovirus-mediated transfer of VEGF hastens functional hepatic recovery in lean, and more importantly also, in obese mice after partial hepatectomy.
Redaelli
Claudio A
CA
Department of Visceral and Transplantation Surgery, Inselspital, University of Bern, Bern, Switzerland.
Semela
David
D
Carrick
Francine E
FE
Ledermann
Monika
M
Candinas
Daniel
D
Sauter
Bernhard
B
Dufour
Jean-François
JF
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015703:Antigens, CD; D001835:Body Weight; D001944:Breath Tests; D000071063:Endoglin; D005234:Fatty Liver / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D005690:Galactose / Q000378:metabolism; D015316:Genetic Therapy; D006498:Hepatectomy; D022781:Hepatocytes / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007763:Lac Operon; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000503:physiopathology*; D009929:Organ Size; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface; D020127:Recovery of Function; D014157:Transcription Factors / Q000235:genetics; D019076:Transgenes; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D005690:Galactose