Comparison of Endothelial Cell Proliferation in Normal Liver and Adipose Tissue in B6C3F1 Mice, F344 Rats, and Humans

Peroxisome proliferator-activated receptor gamma (PPARγ) and dual PPARα and γ agonists have been developed for use in the treatment of diabetes and hyperlipidemias. Vascular tumors were increased in mice treated with some PPAR agonists, but not in rats. Spontaneous hemangiosarcomas are common in sev...

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Bibliographic Details
Published in:Toxicologic pathology 2007-12, Vol.35 (7), p.904-909
Main Authors: Ohnishi, Takamasa, Arnold, Lora L., Clark, Nicol M., Wisecarver, James L., Cohen, Samuel M.
Format: Article
Language:English
Subjects:
Adipose Tissue - cytology
Adult
Animals
Cell Proliferation
Endothelial Cells - cytology
Female
Hemangiosarcoma - etiology
Humans
Liver - cytology
Male
Mice
Middle Aged
Platelet Endothelial Cell Adhesion Molecule-1 - analysis
PPAR gamma - agonists
Rats
Rats, Inbred F344
Species Specificity
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Summary:Peroxisome proliferator-activated receptor gamma (PPARγ) and dual PPARα and γ agonists have been developed for use in the treatment of diabetes and hyperlipidemias. Vascular tumors were increased in mice treated with some PPAR agonists, but not in rats. Spontaneous hemangiosarcomas are common in several strains of mice, uncommon in rats, and rarely occur in humans. The objective of this study was to determine the endothelial cell proliferation rate in liver and adipose tissue of B6C3F1 mice, F344 rats, and humans to aid in investigations of the genesis and development of hemangiosarcoma formation, and to determine the relevance of the increased endothelial cell proliferation rate in drug-treated rodents in assessing the risk of these drugs in humans. We determined the endothelial cell labeling index (LI) in untreated mice, rats, and humans, in normal liver, brown fat (rats and mice only) and white fat by dual immunohistochemistry of CD31 and Ki-67. The LI, highest in mice and lowest in humans, was statistically significantly greater in the mouse compared to the human and rat. The increased rate of spontaneous or PPAR agonist-induced hemangiosarcoma formation in mice may be related to the higher background endothelial cell proliferation rate compared to rats and humans.
ISSN:0192-6233
1533-1601
DOI:10.1080/01926230701748081