These authors contributed equally to this work.
Liver Failure/Cirrhosis/Portal Hypertension
Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats
Article first published online: 18 JUN 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 60, Issue 2, pages 633–647, August 2014
How to Cite
Coch, L., Mejias, M., Berzigotti, A., Garcia-Pras, E., Gallego, J., Bosch, J., Mendez, R. and Fernandez, M. (2014), Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats. Hepatology, 60: 633–647. doi: 10.1002/hep.26995
Potential conflict of interest: Nothing to report.
Supported by grants from the Ministerio de Economia y Competitividad (SAF2008-02461 and SAF2011-29491 to M.F.; PS09/01261 and ACI2009-0938 to J.B.; BFU2011-30121 and Consolider RNAREG CSD2009-00080 to R.M.), AGAUR (SGR1108 to J.B.), AICR (11-0086 to R.M.) and Generalitat de Catalunya (2009SGR1436 to R.M.). The CIBERehd is an initiative from the Instituto de Salud Carlos III.
See Editorial on Page 458
- Issue published online: 22 JUL 2014
- Article first published online: 18 JUN 2014
- Accepted manuscript online: 4 JAN 2014 07:17AM EST
- Manuscript Accepted: 28 DEC 2013
- Manuscript Received: 12 SEP 2013
Pathological angiogenesis represents a critical hallmark for chronic liver diseases. Understanding the mechanisms regulating angiogenesis is essential to develop new therapeutic strategies that specifically target pathological angiogenesis without affecting physiological angiogenesis. Here we investigated the contribution and therapeutic impact of the endogenous angioinhibitor vasohibin-1 in portal hypertension and cirrhosis. The spatiotemporal expression profiling of vasohibin-1 and its relationship with vascular endothelial growth factor (VEGF), angiogenesis, and fibrogenesis was determined through the analysis of human cirrhotic liver specimens, widely accepted in vivo animal models of portal hypertension and cirrhosis, and in vitro angiogenesis assays. Effects of vasohibin-1 overexpression by adenoviral-mediated gene transfer on angiogenesis, fibrogenesis, and portal hypertension-associated hemodynamic alterations were also studied in rats. We found that vasohibin-1 and VEGF are up-regulated, in mesentery and liver, in cirrhotic and precirrhotic portal hypertensive rats and cirrhosis patients. Our results are consistent with vasohibin-1/VEGF cascades being spatially and temporally coordinated through a negative-feedback loop driving pathological angiogenesis. Paradoxically, further overexpression of vasohibin-1 by adenoviral gene transfer exerts multifold beneficial effects in portal hypertension and cirrhosis: reduction of pathologic angiogenesis, attenuation of liver fibrogenesis partly mediated through inhibition of hepatic stellate cell activation, and significant decreases in portocollateralization, splanchnic blood flow, portohepatic resistance, and portal pressure. The explanation for this apparent contradiction is that, unlike endogenous vasohibin-1, the ectopic overexpression is not regulated by VEGF and therefore disrupts the negative-feedback loop, thus generating constant, but lower levels of VEGF synthesis sufficient to maintain vascular homeostasis but not pathological angiogenesis. Conclusion: Our study provides evidence that vasohibin-1 regulates portal hypertension-associated pathological angiogenesis and highlights that increasing vasohibin-1 might be a promising novel therapeutic strategy for portal hypertension and cirrhosis. (Hepatology 2014;60:633–647)