Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension.

Chronic liver injury activates hepatic stellate cells (HSCs), which produce collagen and show increased contraction1. Fibrosis and increased contraction of contractile cells lead to portal hypertension and complications2. Additionally, neo-angiogenesis has been identified as a key mechanism in the progression of liver cirrhosis with portal hypertension3. Neo-angiogenesis occurs within the diseased liver and in the splanchnic vascular bed. The extrahepatic angiogenesis further worsens the portal pressure due to higher portal venous inflow and by opening venous collaterals3,4,5. Interestingly, extrahepatic angiogenesis also occurs in absence of cirrhosis, for example due to portal vein obstruction or thrombosis6,7,8. However, there is scant information about the differences between cirrhotic and non-cirrhotic portal hypertensive angiogenesis. Statins decrease fibrosis and lower portal hypertension in animals and humans mainly by blunting the RhoA/Rho-kinase-pathway in myofibroblastic HSCs9,10,11,12,13,14,15,16. Interestingly, RhoA/Rho-kinase-pathway seems to also 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). Figure 1 Simplified canonical and non-canonical hegdehog pathway and their potential implication in portal hypertension. In liver cirrhosis, also canonical Hh-pathway is activated19. In this pathway, the cell surface receptor Patched-1 inhibits Smoothened. When Hh ligands bind Patched-1, Smoothened translocates and activates Gli transcription factors. Previous studies described that Hh pathway leads to the progression of liver diseases. Thereby, Gli enhances transcription of downstream target genes, which activate HSCs and promote the survival of these fibrogenic and contractile cells19,20,21,22,23,24,25. Interestingly, it has been described that statin treatment might decrease Hh activation26,27. However, 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. Therefore, 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.