Research Article| Volume 40, ISSUE 2, P305-312, February 2004

Effect of vascular endothelial growth factor on functional recovery after hepatectomy in lean and obese mice



      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.



      VEGF (vascular endothelial growth factor), HIF (hypoxia inducible factor)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Redaelli C.A
        • Wagner M
        • Krahenbuhl L
        • Gloor B
        • Schilling M.K
        • Dufour J.F
        • Buchler M.W
        Liver surgery in the era of tissue-preserving resections: early and late outcome in patients with primary and secondary hepatic tumors.
        World J Surg. 2002; 26: 9
        • Selzner M
        • Clavien P.A
        Fatty liver in liver transplantation and surgery.
        Semin Liver Dis. 2001; 21: 105-113
        • Selzner M
        • Clavien P.A
        Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway.
        Hepatology. 2000; 31: 35-42
        • Behrns K.E
        • Tsiotos G.G
        • DeSouza N.F
        • Krishna M.K
        • Ludwig J
        • Nagorney D.M
        Hepatic steatosis as a potential risk factor for major hepatic resection.
        J Gastrointest Surg. 1998; 2: 292-298
        • Belghiti J
        • Hiramatsu K
        • Benoist S
        • Massault P
        • Sauvanet A
        • Farges O
        Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection.
        J Am Coll Surg. 2000; 191: 38-46
        • Sato T
        • El-Assal O.N
        • Ono T
        • Yamanoi A
        • Dhar D.K
        • Nagasue N
        Sinusoidal endothelial cell proliferation and expression of angiopoietin/Tie family in regenerating rat liver.
        J Hepatol. 2001; 34: 690-698
        • Martinez-Hernandez A
        • Amenta P.S
        The extracellular matrix in hepatic regeneration.
        Fed Am Soc Exp Biol J. 1995; 9: 1401-1410
        • Taniguchi E
        • Sakisaka S
        • Matsuo K
        • Tanikawa K
        • Sata M
        Expression and Role of Vascular Endothelial Growth Factor in Liver Regeneration After Partial Hepatectomy in Rats.
        J Histochem Cytochem. 2001; 49: 121-130
        • Mochida S
        • Ishikawa K
        • Inao M
        • Shibuya M
        • Fujiwara K
        Increased expressions of vascular endothelial growth factor and its receptors, flt-1 and KDR/flk-1, in regenerating rat liver.
        Biochem Biophys Res Commun. 1996; 226: 176-179
        • Ross M.A
        • Sander C.M
        • Kleeb T.B
        • Watkins S.C
        • Stolz D.B
        Spatiotemporal expression of angiogenesis growth factor receptors during the revascularization of regenerating rat liver.
        Hepatology. 2001; 34: 1135-1148
        • Drixler T.A
        • Vogten M.J
        • Ritchie E.D
        • Van Vroonhoven T.J
        • Gebbink M.F
        • Voest E.E
        Borel Rinkes IH.
        Liver regeneration is an angiogenesis- associated phenomenon. Ann Surg. 2002; 236: 703-712
        • Sauter B.V
        • Martinet O
        • Zhang W.J
        • Mandeli J
        • Woo S.L
        Adenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases.
        Proc Natl Acad Sci USA. 2000; 97: 4802-4807
        • Bircher J
        Quantitative assessment of deranged hepatic function: a missed opportunity?.
        Seminars in Liver Disease. 1983; 3: 275-284
        • Gross Jr, J.B
        • Reichen J
        • Zeltner T.B
        • Zimmermann A
        The evolution of changes in quantitative liver function tests in a rat model of biliary cirrhosis: correlation with morphometric measurement of hepatocyte mass.
        Hepatology. 1987; 7: 457-463
        • Higgins G
        • Anderson R
        Restoration of the liver of the white rat following partial surgical removal.
        Arch Pathol. 1931; 12: 186-202
        • Dufour J.F
        • Luthi M
        • Forestier M
        • Magnino F
        Expression of inositol 1,4,5-trisphosphate receptor isoforms in rat cirrhosis.
        Hepatology. 1999; 30: 1018-1026
        • Wong A.K
        • Alfert M
        • Castrillon D.H
        • Shen Q
        • Holash J
        • Yancopoulos G.D
        • Chin L
        Excessive tumor-elaborated VEGF and its neutralization define a lethal paraneoplastic syndrome.
        Proc Natl Acad Sci USA. 2001; 98: 7481-7486
        • Zoli M
        • Marchesini G
        • Melli A
        • Viti G
        • Marra A
        • Marrano D
        • Pisi E
        Evaluation of liver volume and liver function following hepatic resection in man.
        Liver. 1986; 6: 286-291
        • Jansen P.L
        • Chamuleau R.A
        • van Leeuwen D.J
        • Schipper H.G
        • Busemann-Sokole E
        • van der Heyde M.N
        Liver regeneration and restoration of liver function after partial hepatectomy in patients with liver tumors.
        Scand J Gastroenterol. 1990; 25: 112-118
        • Yildirim S.I
        • Poulsen H.E
        Quantitative liver functions after 70% hepatectomy.
        Eur J Clin Invest. 1981; 11: 469-472
        • Assy N
        • Spira G
        • Paizi M
        • Shenkar L
        • Kraizer Y
        • Cohen T
        • Neufeld G
        • et al.
        Effect of vascular endothelial growth factor on hepatic regenerative activity following partial hepatectomy in rats.
        J Hepatol. 1999; 30: 911-915
        • LeCouter J
        • Moritz D.R
        • Li B
        • Phillips G.L
        • Liang X.H
        • Gerber H.P
        • Hillan K.J
        • et al.
        Angiogenesis-independent endothelial protection of liver: role of VEGFR-1.
        Science. 2003; 299: 890-893
        • Alavi A
        • Hood J.D
        • Frausto R
        • Stupack D.G
        • Cheresh D.A
        Role of Raf in vascular protection from distinct apoptotic stimuli.
        Science. 2003; 301: 94-96
        • Harris A.L
        Hypoxia–a key regulatory factor in tumour growth.
        Nat Rev Cancer. 2002; 2: 38-47
        • Su A.I
        • Guidotti L.G
        • Pezacki J.P
        • Chisari F.V
        • Schultz P.G
        Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice.
        Proc Natl Acad Sci USA. 2002; 99: 11181-11186
        • Sanchez-Elsner T
        • Botella L.M
        • Velasco B
        • Langa C
        • Bernabeu C
        Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways.
        J Biol Chem. 2002; 277: 43799-43808
        • Duff S
        • Li C
        • Garland J
        • Kumar S
        CD105 is important for angiogenesis: evidence and potential applications.
        Fed Am Soc Exp Biol J. 2003; 17: 984-992
        • Sabba C
        • Cirulli A
        • Rizzi R
        • Pasculli G
        • Gallitelli M
        • Specchia G
        • Liso V
        Angiogenesis and hereditary hemorrhagic telangiectasia. Rendu–Osler–Weber disease.
        Acta Haematol. 2001; 106: 214-219
        • Li C
        • Issa R
        • Kumar P
        • Hampson I.N
        • Lopez-Novoa J.M
        • Bernabeu C
        • Kumar S
        CD105 prevents apoptosis in hypoxic endothelial cells.
        J Cell Sci. 2003; 116: 2677-2685
        • Sierra-Honigmann M.R
        • Nath A.K
        • Murakami C
        • Garcia-Cardena G
        • Papapetropoulos A
        • Sessa W.C
        • Madge L.A
        • et al.
        Biological action of leptin as an angiogenic factor.
        Science. 1998; 281: 1683-1686
        • Rao M.S
        • Papreddy K
        • Abecassis M
        • Hashimoto T
        Regeneration of liver with marked fatty change following partial hepatectomy in rats.
        Dig Dis Sci. 2001; 46: 1821-1826
        • Picard C
        • Lambotte L
        • Starkel P
        • Sempoux C
        • Saliez A
        • Van den Berge V
        • Horsmans Y
        Steatosis is not sufficient to cause an impaired regenerative response after partial hepatectomy in rats.
        J Hepatol. 2002; 36: 645-652