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Liver Failure/Cirrhosis/Portal Hypertension
Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats†
Article first published online: 24 JUL 2007
Copyright © 2007 American Association for the Study of Liver Diseases
Volume 46, Issue 4, pages 1208–1217, October 2007
How to Cite
Fernandez, M., Mejias, M., Garcia-Pras, E., Mendez, R., Garcia-Pagan, J. C. and Bosch, J. (2007), Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats. Hepatology, 46: 1208–1217. doi: 10.1002/hep.21785
Potential conflict of interest: Nothing to report.
- Issue published online: 25 SEP 2007
- Article first published online: 24 JUL 2007
- Manuscript Accepted: 18 APR 2007
- Manuscript Received: 5 DEC 2006
- Ministerio de Educacion y Ciencia. Grant Number: SAF2005-05825
- Instituto de Salud Carlos III. Grant Numbers: PI02739, PI040655, CO3/02
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.)