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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Fernandez
Mercedes
M
Hepatic Hemodynamic Laboratory, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. mercefernandez@ub.es
Mejias
Marc
M
Angermayr
Bernhard
B
Garcia-Pagan
Juan Carlos
JC
Rodés
Juan
J
Bosch
Jaime
J
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000503:physiopathology; D003097:Collateral Circulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006975:Hypertension, Portal / Q000150:complications* / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009389:Neovascularization, Pathologic / Q000209:etiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000187:drug effects; D011168:Portal System / Q000503:physiopathology*; D011169:Portal Vein / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013152:Splanchnic Circulation / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014655:Vascular Resistance / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D007211:Indoles; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C116890:Semaxinib; D040301:Vascular Endothelial Growth Factor Receptor-2