Submitted on December 20, 2005
Accepted on March 20, 2006
Vascular Endothelial Growth Factor and Hepatocyte Regeneration in Acetaminophen Toxicity
Brian Donahower1, Sandra S McCullough2, Richard C Kurten3, Laura W Lamps4, Pippa M Simpson2, Jack A. Hinson1, and Laura P James5*
1 Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
2 Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States; Arkansas Childrens Hospital Research Institute, Little Rock, Arkansas, United States
3 Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States; Arkansas Childrens Hospital Research Institute, Little Rock, Arkansas, United States
4 Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
5 Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States; Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States; Arkansas Childrens Hospital Research Institute, Little Rock, Arkansas, United States
* To whom correspondence should be addressed. E-mail: jameslaurap{at}uams.edu.
Vascular endothelial growth factor (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 sacrificed at various time points that reflect both the acute and recovery stages of toxicity. VEGF-A protein levels were increased 7 fold at 8 hrs and followed the development of hepatotoxicity. VEGF receptor 1, 2, and 3 (VEGFR1, VEGFR2, and VEGFR3) expression increased throughout the time course, with maximal expression at 48, 8, and 72 hrs, respectively. Treatment with the VEGF receptor inhibitor, SU5416 (25 mg/kg IP at 3 hrs), had no effect on toxicity at 6 or 24 hours. 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 hrs) resulted in decreased expression of proliferating cell nuclear antigen (PCNA), a marker of cellular proliferation. Expression of platelet endothelial cell adhesion molecule (PECAM), a measure of small vessel density, and endothelial nitric oxide synthase (NOS), a downstream target of VEGFR2, were increased at 48 and 72 hrs 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.
