Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats

Portal hypertension is characterized by the development of a hyperdynamic splanchnic circulation. To determine whether this process is angiogenesis-dependent, we assessed the effects of SU5416, a specific inhibitor of VEGF receptor-2, in portal hypertensive rats. Rats with portal hypertension induce...

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Bibliographic Details
Published in:Journal of hepatology 2005-07, Vol.43 (1), p.98-103
Main Authors: Fernandez, Mercedes, Mejias, Marc, Angermayr, Bernhard, Garcia-Pagan, Juan Carlos, Rodés, Juan, Bosch, Jaime
Format: Article
Language:English
Subjects:
Angiogenesis
Angiogenesis Inhibitors - pharmacology
Animals
Arterioles - physiopathology
Biological and medical sciences
Collateral Circulation - drug effects
Gastroenterology. Liver. Pancreas. Abdomen
Hemodynamics - drug effects
Hyperdynamic splanchnic circulation
Hypertension, Portal - complications
Hypertension, Portal - physiopathology
Indoles - pharmacology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Male
Medical sciences
Neovascularization, Pathologic - etiology
Other diseases. Semiology
Platelet Endothelial Cell Adhesion Molecule-1 - drug effects
Portal hypertension
Portal System - physiopathology
Portal Vein - physiopathology
Portal-systemic collateral vessels
Protein Kinase Inhibitors - pharmacology
Pyrroles - pharmacology
Rats
Rats, Sprague-Dawley
Regional Blood Flow - drug effects
Splanchnic Circulation - drug effects
SU5416
Vascular endothelial growth factor
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 - metabolism
Vascular Resistance - drug effects
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Summary:Portal hypertension is characterized by the development of a hyperdynamic splanchnic circulation. To determine whether this process is angiogenesis-dependent, we assessed the effects of SU5416, a specific inhibitor of VEGF receptor-2, in portal hypertensive rats. Rats with portal hypertension induced by partial portal vein ligation were treated with SU5416 or vehicle during 5 days. Then, hemodynamic studies were performed using radioactive microspheres. Protein expressions of CD31, VEGF receptor-2 and VEGF were also determined by Western blotting. Treatment of portal hypertensive rats with SU5416 resulted in a significant and marked decrease (by 44%) in portal venous inflow, and increases in splanchnic arteriolar resistance (by 68%) and portal venous resistance (by 93%). In addition, SU5416 administration significantly inhibited the formation of portal-systemic collateral vessels (52% inhibition), as well as the splanchnic CD31 and VEGF receptor-2 protein expressions in portal hypertensive rats, compared with those receiving vehicle. This study demonstrates that the development of hyperdynamic splanchnic circulation and the formation of portal-systemic collateral vessels in portal hypertensive rats are angiogenesis-dependent processes that can be markedly inhibited by blockade of the VEGF signaling pathway. Therefore, modulation of angiogenesis may represent a potential target in the treatment of portal hypertension.
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2005.02.022