These authors shared first authorship
Overexpression of angiopoietin-2 in rats and patients with liver fibrosis. Therapeutic consequences of its inhibition
Article first published online: 11 MAR 2014
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
How to Cite
Pauta, M., Ribera, J., Melgar-Lesmes, P., Casals, G., Rodríguez-Vita, J., Reichenbach, V., Fernandez-Varo, G., Morales-Romero, B., Bataller, R., Michelena, J., Altamirano, J., Jiménez, W. and Morales-Ruiz, M. (2014), Overexpression of angiopoietin-2 in rats and patients with liver fibrosis. Therapeutic consequences of its inhibition. Liver International. doi: 10.1111/liv.12505
- Article first published online: 11 MAR 2014
- Accepted manuscript online: 19 FEB 2014 10:33AM EST
- Manuscript Accepted: 12 FEB 2014
- Manuscript Received: 10 JUL 2013
- Ministerio de Economia y Competitividad. Grant Numbers: SAF2010-19025, SAF2012-35979
- Fondo de Investigación Sanitaria. Grant Number: FIS PI080237
- AGAUR. Grant Number: 2009 SGR 1496
- MINECO. Grant Number: BES-2007-16909
- Instituto de Salud Carlos III
- chronic liver disease;
- liver sinusoidal endothelial cells;
- portal hypertension
Background & Aims
Studies in experimental models of cirrhosis showed that anti-angiogenic treatments may be effective for the treatment of liver fibrosis. In this context, angiopoietins are potential therapeutic targets as they are involved in the maintenance and stabilization of newly formed blood vessels. In addition, angiopoietin-2 is expressed in fibrotic livers and its inhibition in tumours results in vessel stability. Therefore, our study was aimed to assess the therapeutic utility of inhibiting angiopoietin-2.
Circulating levels of angiopoietin-1 and angiopoietin-2 were quantified by ELISA in CCl4-treated rats and in patients with cirrhosis. In vivo blockade of angiopoietin-2 in rats with liver fibrosis was performed with a chemically programmed antibody, CVX-060.
High levels of angiopoietin-2 were found in the systemic and suprahepatic circulation of cirrhotic patients and the ratio angiopoietin-1/angiopoietin-2 inversely correlated with prognostic models for alcoholic liver disease. Chronic treatment of CCl4-treated rats with CVX-060 was associated with a significant decrease in inflammatory infiltrate, normalization of the hepatic microvasculature and reduction in VCAM-1 vascular expression. The anti-angiopoietin-2 treatment was also associated with less liver fibrosis and with lower levels of circulating transaminases. CVX-060 treatment was not associated with either vascular pruning in healthy tissue or compensatory overexpression of VEGF.
Inhibition of angiopoietin-2 is an effective and safe treatment for liver fibrosis in CCl4-treated rats, acting mainly through the induction of vessel normalization and the attenuation of hepatic inflammatory infiltrate. Therefore, inhibition of angiopoietin-2 offers a therapeutic alternative for liver fibrosis.