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Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity. Am J Physiol Gastrointest Liver Physiol 2006 Jul;291(1):G102-9

Date

03/28/2006

Pubmed ID

16565415

DOI

10.1152/ajpgi.00575.2005

Scopus ID

2-s2.0-33745804516 (requires institutional sign-in at Scopus site)   65 Citations

Abstract

VEGF or VEGF-A is a major regulator of angiogenesis and has been recently shown to be important in organ repair. The potential role of VEGF in acetaminophen (APAP)-induced hepatotoxicity and recovery was investigated in B6C3F1 male mice. Mice were treated with APAP (300 mg/kg ip) and killed at various time points that reflect both the acute and recovery stages of toxicity. VEGF-A protein levels were increased 7-fold at 8 h and followed the development of hepatotoxicity. VEGF receptor 1, 2, and 3 (VEGFR1, VEGFR2, and VEGFR3, respectively) expression increased throughout the time course, with maximal expression at 48, 8, and 72 h, respectively. Treatment with the VEGF receptor inhibitor SU5416 (25 mg/kg ip at 3 h) had no effect on toxicity at 6 or 24 h. In further studies, the role of SU5416 on the late stages of toxicity was examined. Treatment of mice with APAP and SU5416 (25 mg/kg ip at 3 h) resulted in decreased expression of PCNA, a marker of cellular proliferation. Expression of platelet endothelial cell adhesion molecule, a measure of small vessel density, and endothelial nitric oxide synthase (NOS), a downstream target of VEGFR2, were increased at 48 and 72 h following toxic doses of APAP, and treatment with SU5416 decreased their expression. These data indicate that endogenous VEGF is critically important to the process of hepatocyte regeneration in APAP-induced hepatotoxicity in the mouse.

Author List

Donahower B, McCullough SS, Kurten R, Lamps LW, Simpson P, Hinson JA, James LP

Author

Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acetaminophen
Analgesics, Non-Narcotic
Animals
Apoptosis
Cells, Cultured
Liver Failure, Acute
Liver Regeneration
Male
Mice
Receptors, Vascular Endothelial Growth Factor
Signal Transduction
Toxicity Tests
Vascular Endothelial Growth Factor A