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.
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-1α (HIF-1α) was assessed by quantitative RT-PCR and for endoglin also by immunohistochemistry.
After 2/3 hepatectomy, VEGFgene transfer increased galactose elimination capacity in lean and ob/ob mice. HIF-1α, 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-1α and increased flk1 response in lean mice.
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.
Abbreviations:VEGF (vascular endothelial growth factor), HIF (hypoxia inducible factor)
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Accepted: October 30, 2003
Received in revised form: September 18, 2003
Received: April 6, 2003MS 351
© 2003 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.