Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet‐derived growth factor blockade in rats

Vascular endothelial growth factor (VEGF) and platelet‐derived growth factor (PDGF) pathways are crucial to angiogenesis, a process that contributes significantly to the pathogenesis of portal hypertension. This study determined the effects of inhibition of VEGF and/or PDGF signaling on hyperdynamic...

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Published in:Hepatology (Baltimore, Md.) Md.), 2007-10, Vol.46 (4), p.1208-1217
Main Authors: Fernandez, Mercedes, Mejias, Marc, Garcia‐Pras, Ester, Mendez, Raul, Garcia‐Pagan, Juan Carlos, Bosch, Jaime
Format: Article
Language:English
Subjects:
Animals
Arterial hypertension. Arterial hypotension
Benzamides
Biological and medical sciences
Blood and lymphatic vessels
Cardiology. Vascular system
Disease Models, Animal
Drug Therapy, Combination
Gastroenterology. Liver. Pancreas. Abdomen
Hypertension, Portal - drug therapy
Hypertension, Portal - metabolism
Hypertension, Portal - physiopathology
Imatinib Mesylate
Immunosuppressive Agents - therapeutic use
Ligation
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Male
Medical sciences
Mesenteric Artery, Superior - physiopathology
Neovascularization, Pathologic - drug therapy
Neovascularization, Pathologic - metabolism
Nervous system (semeiology, syndromes)
Nervous system as a whole
Neurology
Other diseases. Semiology
Piperazines - therapeutic use
Platelet-Derived Growth Factor - antagonists & inhibitors
Platelet-Derived Growth Factor - metabolism
Portal Vein - physiopathology
Protein Kinase Inhibitors - therapeutic use
Pyrimidines - therapeutic use
Rats
Rats, Sprague-Dawley
Regional Blood Flow - physiology
Signal Transduction - physiology
Sirolimus - therapeutic use
Splanchnic Circulation - physiology
Vascular Endothelial Growth Factor A - antagonists & inhibitors
Vascular Endothelial Growth Factor A - metabolism
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Summary:Vascular endothelial growth factor (VEGF) and platelet‐derived growth factor (PDGF) pathways are crucial to angiogenesis, a process that contributes significantly to the pathogenesis of portal hypertension. This study determined the effects of inhibition of VEGF and/or PDGF signaling on hyperdynamic splanchnic circulation and portosystemic collateralization in rats with completely established portal hypertension, thus mimicking the situation in patients. Portal vein–ligated rats were treated with rapamycin (VEGF signaling inhibitor), Gleevec (PDGF signaling inhibitor), or both simultaneously when portal hypertension was already fully developed. Hemodynamic studies were performed by transit‐time flowmetry. The extent of portosystemic collaterals was measured by radioactive microspheres. The expression of angiogenesis mediators was determined by Western blotting and immunohistochemistry. Combined inhibition of VEGF and PDGF signaling significantly reduced splanchnic neovascularization (i.e., CD31 and VEGFR‐2 expression) and pericyte coverage of neovessels (that is, α‐smooth muscle actin and PDGFR‐β expression) and translated into hemodynamic effects as marked as a 40% decrease in portal pressure, a 30% decrease in superior mesenteric artery blood flow, and a 63% increase in superior mesenteric artery resistance, yielding a significant reversal of the hemodynamic changes provoked by portal hypertension in rats. Portosystemic collateralization was reduced as well. Conclusions: Our results provide new insights into how angiogenesis regulates portal hypertension by demonstrating that the maintenance of increased portal pressure, hyperkinetic circulation, splanchnic neovascularization, and portosystemic collateralization is regulated by VEGF and PDGF in portal hypertensive rats. Importantly, these findings also suggest that an extended antiangiogenic strategy (that is, targeting VEGF/endothelium and PDGF/pericytes) may be a novel approach to the treatment of portal hypertension. (HEPATOLOGY 2007.)
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.21785