Abstract
Liver cirrhosis but also portal vein obstruction cause portal hypertension (PHT) and angiogenesis. This study investigated the differences of angiogenesis in cirrhotic and non-cirrhotic PHT with special emphasis on the canonical (Shh/Gli) and non-canonical (Shh/RhoA) hedgehog pathway. Cirrhotic (bile duct ligation/BDL; CCl4 intoxication) and non-cirrhotic (partial portal vein ligation/PPVL) rats received either atorvastatin (15 mg/kg; 7d) or control chow before sacrifice. Invasive hemodynamic measurement and Matrigel implantation assessed angiogenesis in vivo. Angiogenesis in vitro was analysed using migration and tube formation assay. In liver and vessel samples from animals and humans, transcript expression was analyzed using RT-PCR and protein expression using Western blot. Atorvastatin decreased portal pressure, shunt flow and angiogenesis in cirrhosis, whereas atorvastatin increased these parameters in PPVL rats. Non-canonical Hh was upregulated in experimental and human liver cirrhosis and was blunted by atorvastatin. Moreover, atorvastatin blocked the non-canonical Hh-pathway RhoA dependently in activated hepatic steallate cells (HSCs). Interestingly, hepatic and extrahepatic Hh-pathway was enhanced in PPVL rats, which resulted in increased angiogenesis. In summary, statins caused contrary effects in cirrhotic and non-cirrhotic portal hypertension. Atorvastatin inhibited the non-canonical Hh-pathway and angiogenesis in cirrhosis. In portal vein obstruction, statins enhanced the canonical Hh-pathway and aggravated PHT and angiogenesis.
Highlights
Atorvastatin treatment led to a dramatic augmentation of shunt flow and cardiac output in Partial portal vein ligation (PPVL) rats compared to untreated PPVL rats (Fig. 2E–G)
To the activation of Hh-signaling in the respective livers, angiogenesis is blunted in cirrhosis after atorvastatin treatment, but enhanced in non-cirrhotic portal hypertension, we investigated the role of canonical and non-canonical Hh-signaling in the extrahepatic vessels
This study shows for the first time, that the mechanisms of neo-angiogenesis in cirrhotic and non-cirrhotic portal hypertension are different
Summary
Statins decrease fibrosis and lower portal hypertension in animals and humans mainly by blunting the RhoA/Rho-kinase-pathway in myofibroblastic HSCs9–16. RhoA/Rho-kinase-pathway seems to play a role in the non-canonical Hedgehog-signaling (Hh)[17,18]. This crosstalk between RhoA/ Rho-kinase and Hh-pathway might be mediated by Shh and is Gli-independent (Fig. 1A). Canonical Hh-pathway is activated[19] In this pathway, the cell surface receptor Patched-1 inhibits Smoothened. It has been described that statin treatment might decrease Hh activation[26,27] It is unknown whether statins interfere with canonical or with the non-canonical Hh signaling and which is their role in angiogenesis induced by portal hypertension. We investigated (i) the pathophysiological differences in angiogenesis induced by cirrhotic or non-cirrhotic portal hypertension, (ii) the effects of statins on angiogenesis in cirrhotic and non-cirrhotic portal hypertension and (iii) their role on the canonical and non-canonical Hh-pathway in portal hypertension
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