title: Pioglitazone decreases portosystemic shunting by modulating inflammation and angiogenesis in cirrhotic and non-cirrhotic portal hypertensive rats.
abstract: OBJECTIVE
  Development of the portal-hypertensive syndrome is mediated by splanchnic inflammation and neoangiogenesis. Since peroxisome proliferator-activated receptor gamma (PPARγ) agonists like pioglitazone (PIO) regulate inflammatory response and inhibit angiogenesis in endothelial cells, we evaluated PIO as treatment for experimental portal hypertension.
  
  
  METHODS
  PIO (10 mg/kg) or vehicle (VEH) was administered from day 21-28 after bile duct ligation (BDL), from day 0-7 after partial portal vein ligation (PPVL) or sham-operation (SO), respectively. After treatment, systemic hemodynamics, splanchnic blood flow (SMABF), portal pressure (PP), and portosystemic shunting (PSS) were assessed. Splanchnic and hepatic tissues were analyzed for angiogenic and inflammatory markers.
  
  
  RESULTS
  BDL and PPVL showed significantly increased PP, SMABF, and PSS compared to SO-VEH rats. While PIO treatment did not decrease PP or SMABF, PSS was significantly reduced both in cirrhotic (BDL-VEH: 71% to BDL-PIO: 41%; p<0.001) and non-cirrhotic (PPVL-VEH: 62% to PPVL-PIO: 40%; p=0.041) rats. PIO (10 μM, in vitro) inhibited endothelial cell migration and significantly increased PPARγ activity in vivo. In BDL rats, PIO decreased hepatic mRNA levels of PPARγ (p=0.01) and PlGF (p=0.071), and splanchnic mRNA expression of PPARγ (p=0.017), PDGFβ (p=0.053) and TNFα (p=0.075). Accordingly, splanchnic protein expression of PPARγ (p=0.032), VEGFR2 (p=0.035), CD31 (p=0.060) and PDGFβ (p=0.066) were lower in BDL-PIO vs. BDL-VEH animals. In PPVL rats, PIO treatment decreased splanchnic gene expression of Ang2 (-12.4 fold), eNOS (-9.3 fold), PDGF (-7.0 fold), PlGF (-11.9 fold), TGFb (-8.3 fold), VEGF-A (-11.3 fold), VEGFR1 (-5.9 fold), IL1b (-14.4 fold), and IL6 (-9.6 fold).
  
  
  CONCLUSIONS
  Pioglitazone treatment decreases portosystemic shunting via modulation of splanchnic inflammation and neoangiogenesis. Pioglitazone should be assessed for potential beneficial effects in patients with portosystemic collaterals due to portal hypertension.
authors: Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, Medical University Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Vienna, Austria.
authors: Philipp
authors: P
authors: Schwabl
authors: Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, Medical University Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Vienna, Austria.
authors: Berit A
authors: BA
authors: Payer
authors: Edwin L. Steele Laboratory of Tumor Biology, Dept. of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors: Jelena
authors: J
authors: Grahovac
authors: Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine I, University of Bonn, Germany.
authors: Sabine
authors: S
authors: Klein
authors: Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, Medical University Vienna, Austria.
authors: Thomas
authors: T
authors: Horvatits
authors: Dept. of Nuclear Medicine, Medical University Vienna, Austria.
authors: Markus
authors: M
authors: Mitterhauser
authors: Dept. of Pathology, Medical University Vienna, Austria.
authors: Judith
authors: J
authors: Stift
authors: Edwin L. Steele Laboratory of Tumor Biology, Dept. of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors: Yves
authors: Y
authors: Boucher
authors: Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine I, University of Bonn, Germany.
authors: Jonel
authors: J
authors: Trebicka
authors: Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, Medical University Vienna, Austria.
authors: Michael
authors: M
authors: Trauner
authors: Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, Medical University Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Vienna, Austria.
authors: Bernhard
authors: B
authors: Angermayr
authors: Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, Medical University Vienna, Austria.
authors: Valentin
authors: V
authors: Fuhrmann
authors: Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, Medical University Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Vienna, Austria; Edwin L. Steele Laboratory of Tumor Biology, Dept. of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors: Thomas
authors: T
authors: Reiberger
authors: Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, Medical University Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Vienna, Austria. Electronic address: markus.peck@meduniwien.ac.at.
authors: Markus
authors: M
authors: Peck-Radosavljevic
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D047495:PPAR gamma / Q000378:metabolism; D000077205:Pioglitazone; D017082:Portal Pressure / Q000187:drug effects* / Q000502:physiology; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: Angiogenesis; BDL; Inflammation; PPARγ; PPVL; Pioglitazone; Portal hypertension; Portosystemic shunting