{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T16:02:08Z","timestamp":1777478528820,"version":"3.51.4"},"reference-count":198,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T00:00:00Z","timestamp":1598572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Liver cirrhosis is a frequent condition with high impact on patients\u2019 life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.<\/jats:p>","DOI":"10.3390\/ijms21176223","type":"journal-article","created":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T09:17:08Z","timestamp":1598606228000},"page":"6223","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6884-0135","authenticated-orcid":false,"given":"Wolfgang","family":"Kreisel","sequence":"first","affiliation":[{"name":"Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6173-9288","authenticated-orcid":false,"given":"Denise","family":"Schaffner","sequence":"additional","affiliation":[{"name":"Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany"},{"name":"Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany"},{"name":"Department of Radiology\u2013Medical Physics, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adhara","family":"Lazaro","sequence":"additional","affiliation":[{"name":"Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7028-3881","authenticated-orcid":false,"given":"Jonel","family":"Trebicka","sequence":"additional","affiliation":[{"name":"Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4716-5016","authenticated-orcid":false,"given":"Irmgard","family":"Merfort","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5082-7979","authenticated-orcid":false,"given":"Annette","family":"Schmitt-Graeff","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3291-884X","authenticated-orcid":false,"given":"Peter","family":"Deibert","sequence":"additional","affiliation":[{"name":"Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1124\/mol.104.001388","article-title":"Cyclic GMP and phosphodiesterase 5 inhibitor therapies: What\u2019s on the horizon?","volume":"66","author":"Lincoln","year":"2004","journal-title":"Mol. 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