CD Laboratory for Portal Hypertension and Fibrosis in Liver Disease

Liver diseases often leads to scarring (fibrosis) of the liver and increased portal vein pressure (portal hypertension), which may cause severe complications such as internal bleeding or abdominal fluid accumulation (ascites). In this CD Laboratory, the molecular mechanisms leading to fibrosis and portal hypertension will be investigated, including research on the role of the enzyme soluble guanylyl cyclase (sGC) in order to develop new therapeutic strategies to improve the treatment of patients with liver disease.

Liver cirrhosis represents an advanced stage of chronic liver disease that is associated with considerable morbidity and mortality mainly related to liver fibrosis and portal hypertension. For some liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) no effective medications are available. However, ongoing liver damage leads to hepatic inflammation, blood vessel remodelling and an accumulation of connective tissue in the liver. The blood vessels of the liver, the so-called sinusoids, lose their characteristic openings (fenestration) in the cell membrane, which significantly increases the resistance to blood flow through the liver and contributes to the development of portal hypertension and of complications such as variceal bleeding or ascites.

This CD Laboratory at the Medical University of Vienna utilizes both sophisticated in vivo models and clinical expertise to characterize molecular mechanisms of portal hypertension and liver fibrosis. The research will be conducted by basic scientists and physician scientists in an multiprofessional and interdisciplinary effort.

One main aim of this CD Laboratory is to investigate the role of sGC in portal hypertension and liver fibrosis. In liver cirrhosis, both the hepatic and the systemic vasculature shows pronounced endothelial dysfunction. These altered liver blood vessels are resistant to vasodilatory substances such as nitric oxide (NO) that is in the human body mainly produced in the internal blood vessel cells, the endothelial cells. However, if the endothelial cells are deficient or resistant to NO - as is the case in liver cirrhosis - the blood vessels in the liver constrict, leading to the development of portal hypertension. The enzyme sGC is currently the only known receptor for NO that can be targeted by drugs. Previous work of CD lab members has shown in animal models with cirrhosis that stimulation of sGC improves both portal hypertension and liver fibrosis. An anti-fibrotic effect of sGC agonists has also been demonstrated in fibrotic diseases of the skin, lungs and kidneys. Furthermore, sGC agonists promote adipose tissue browning, reduce the fat content in the liver and insulin resistance, which also makes sGC agonists a possible therapeutic option for MASLD.

In the first work package, the CD Laboratory investigates the molecular and cellular biology of sGC by studying expression patterns, cellular localisation and enzymatic function in healthy and diseased liver tissue. The sGC signalling pathway and links to with pro-fibrotic mechanisms are analysed in vitro.

In the second work package, the influence of various sGC stimulators and activators on liver fibrosis and portal hypertension will be investigated in cirrhotic animal models. In a liver perfusion setup, intrahepatic dose-dependent hemodynamic effects can be studied in detail. Using telemetry probes, portal vein pressure, arterial blood pressure, heart rate and temperature can be monitored in real time over longer periods of time in the non-anaesthetised animals.

In the third work package, the interplay between sGC activity and hepatic necroinflammation are investigated. This work package will also include research on developing stage-specific and prognostic biomarkers in patients with different severity of portal hypertension and of liver fibrosis..

In the fourth work package, molecular signaling, including the NO/sGC/cGMP pathways will be assessed in an unbiased way by appling RNA sequencing technology both in bulk liver tissues and isolated single cells obtained from diseased liver tissues derived from well-characterized animal models or liver disease patients.

Ultimatley, the researchaims to better understand the role of the NO/sGC/cGMP signalling pathway in portal hypertension and liver fibrosis and to develop clinical applications in terms of diagnostic or prognostic biomarkers and novel therapies for patients with portal hypertension and liver fibrosis.