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.