Pioglitazone reduces portosystemic collateral blood flow via modulation of angiogenesis and inflammation in portal hypertensive rats

P Schwabl; BA Payer; J Grahovac; S Klein; Y Boucher; J Trebicka; B Angermayr; V Fuhrmann; M Trauner; M Peck-Radosavljevic; T Reiberger

doi:10.1055/s-0034-1376041

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

Pioglitazone reduces portosystemic collateral blood flow via modulation of angiogenesis and inflammation in portal hypertensive rats

P Schwabl ¹, BA Payer ¹, J Grahovac ², S Klein ³, Y Boucher ², J Trebicka ³, B Angermayr ¹, V Fuhrmann ¹, M Trauner ¹, M Peck-Radosavljevic ¹ T Reiberger ¹^,², Vienna Hepatic Hemodynamic Lab

¹Medical University of Vienna/Dept. of Internal Medicine III/Div. of Gastroenterology and Hepatology, Vienna, Austria
²Harvard Medical School/Dept. of Radiation Oncology/Edwin L. Steele Laboratory of Tumor Biology, Boston, United States
³Medical University of Bonn/Dept. of Internal Medicine/Div. of Gastroenterology and Hepatology, Bonn, Germany

Abstract

Background and aims:

In portal hypertension, the formation of porto-systemic collaterals is initiated and mediated via angiogenic and inflammatory pathways. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists – such as pioglitazone (PIO) – have been reported to have anti-inflammatory and anti-angiogenic properties. Previously we demonstrated that PIO treatment reduced the portosystemic collateral blood flow (PSCBF) without decreasing portal pressure (PP) in cirrhotic rats. Now we aimed to evaluate the effects of PIO on hemodynamics, angiogenesis, and inflammation in non-cirrhotic portal hypertensive rats.

Methods: Male Sprague-Dawley rats underwent partial portal vein ligation (PPVL; n = 16) or sham operation (SO; n = 16) and received PIO (10 mg/kg/daily gavage) or vehicle (VEH). Hemodynamic measurements were performed after 7 days including mean arterial pressure (MAP), heart rate (HR), portal pressure (PP) and superior mesenteric artery blood flow (SMABF). Portosystemic shunting (PSS) was quantified by colored microspheres. Splanchnic angiogenesis and inflammation was assessed by immunostaining, PCR arrays for mRNA, and Western Blots for protein expression.

Results: PPVL-VEH showed higher PP, SMABF, PSS (62% vs. 3%, p < 0.001) and increased HR compared to SO-VEH rats. In PPVL rats, PIO treatment did not change HR, MAP, PP and SMABF, but significantly reduced PSS from 62% to 40% (p = 0.041). PIO increased the PPARy activity in splanchnic tissue of PPVL-PIO animals and significantly downregulated angiogenic (VEGF, VEGFR2, Angiopoietin 2, PlGF) and inflammatory mediators (CCl2, IFNγ, IL1, IL6). The mesenteric vasculature of portal hypertensive rats presented with low pericyte coverage, increased tortuosity, and a lack of homogenous pericyte-wrapping, which was ameliorated by PIO treatment. In vitro, PIO inhibited endothelial cell migration, without impairing cell viability.

Conclusion: Pioglitazone treatment decreases portosystemic shunting in portal hypertensive rats without affecting systemic hemodynamics or portal pressure. The beneficial effects of PPARy activation are mediated by inhibition of splanchnic inflammation, angiogenesis, and vascular remodeling in the mesenteric vascular bed.