Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension☆

Received 11 August 2008; received in revised form 19 September 2008; accepted 23 September 2008. published online 03 December 2008.

Background/Aims

Angiogenesis is a pathological hallmark of portal hypertension. Although VEGF is considered to be the most important proangiogenic factor in neoangiogenesis, this process requires the coordinated action of a variety of factors. Identification of novel molecules involved in angiogenesis is highly relevant, since they may represent potential new targets to suppress pathological neovascularization in angiogenesis-related diseases like portal hypertension. The apelin/APJ signaling pathway plays a crucial role in angiogenesis. Therefore, we determined whether the apelin system modulates angiogenesis-driven processes in portal hypertension.

Methods

Partial portal vein-ligated rats were treated with the APJ antagonist F13A for seven days. Splanchnic neovascularization and expression of angiogenesis mediators (Western blotting) was determined. Portosystemic collateral formation (microspheres), and hemodynamic parameters (flowmetry) were also assessed.

Results

Apelin and its receptor APJ were overexpressed in the splanchnic vasculature of portal hypertensive rats. F13A effectively decreased, by 52%, splanchnic neovascularization and expression of proangiogenic factors VEGF, PDGF and angiopoietin-2 in portal hypertensive rats. F13A also reduced, by 35%, the formation of portosystemic collateral vessels.

Conclusions

This study provides the first experimental evidence showing that the apelin/APJ system contributes to portosystemic collateralization and splanchnic neovascularization in portal hypertensive rats, presenting a potential novel therapeutic target for portal hypertension.

Associate Editor: C. Merkel

Keywords: Angiogenesis, Vascular endothelial growth factor, Portal pressure, Myosin light chain, P70S6 kinase

Hepatic Hemodynamic Laboratory, Liver Unit, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Ciberehd, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain

Corresponding author. Tel.: +34 93 2275400; fax: +34 93 2279348.

☆ The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this paper.

PII: S0168-8278(08)00765-4

doi:10.1016/j.jhep.2008.09.019

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