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(American Journal of Pathology. 2004;165:889-899.)
© 2004 American Society for Investigative Pathology

Angiopoietin-1 Causes Reversible Degradation of the Portal Microcirculation in Mice

Implications for Treatment of Liver Disease

Nicole L. Ward^*, Alexandra L. Haninec^*, Paul Van Slyke^*, John G. Sled, Celina Sturk^*, R. Mark Henkelman, Ian R. Wanless^¶|| and Daniel J. Dumont^***

From the Divisions of Molecular and Cellular Biology Research^* and Imaging Research, Sunnybrook and Women’s College Research Institute, Toronto; the Departments of Medical Biophysics and Laboratory Medicine and Pathobiology,^¶ the Heart and Stroke/Richard Lewar Centre of Excellence, and the Mouse Imaging Centre, Faculty of Medicine, University of Toronto, Toronto; Toronto-Sunnybrook Regional Cancer Centre,^** Toronto; and the Department of Pathology,|| The Toronto General Hospital, Toronto, Ontario, Canada

In many different liver diseases, such as cirrhosis, degradation of the microcirculation, including obliteration of small portal or hepatic veins contributes to disease-associated portal hypertension. The present study demonstrates the importance of angiogenesis in the establishment of arteriovenous shunts and the accompanying changes to the venous bed. One aspect of angiogenesis involves the branching of new vessels from pre-existing ones, and the molecular mechanisms controlling it are complex and involve a coordinated effort between specific endothelial growth factors and their receptors, including the angiopoietins. We modulated the hepatic vasculature in mice by conditionally expressing angiopoietin-1 in hepatocytes. In mice exposed to angiopoietin-1 during development, arterial sprouting, enlarged arteries, marked loss of portal vein radicles, hepatic vein dilation, and suggestion of arteriovenous shunting were observed. Most importantly, these phenotypic changeswere completely reversed within 14 days of turning off transgene expression. Expression of excess angiopoietin-1 beginning in adulthood did not fully recapitulate the phenotype, but did result in enlarged vessels. Our findings suggest that controlling excessive angiogenesis during liver disease may promote the restoration of the portal vein circuit and aid in the resolution of disease-associated portal hypertension.

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