{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T22:49:25Z","timestamp":1788994165092,"version":"build-2803163510"},"reference-count":129,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,26]],"date-time":"2021-09-26T00:00:00Z","timestamp":1632614400000},"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>The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the \u201cNO-paradox\u201d, referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators\/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum\/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies.<\/jats:p>","DOI":"10.3390\/ijms221910372","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T04:55:33Z","timestamp":1632718533000},"page":"10372","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Cyclic GMP in Liver Cirrhosis\u2014Role in Pathophysiology of Portal Hypertension and Therapeutic Implications"],"prefix":"10.3390","volume":"22","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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Grosse Perdekamp","sequence":"additional","affiliation":[{"name":"Institute of Forensic Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Schmitt-Graeff","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1016\/S0140-6736(14)60121-5","article-title":"Liver cirrhosis","volume":"383","author":"Tsochatzis","year":"2014","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.cld.2019.07.007","article-title":"Portal Hypertension: Pathogenesis and Diagnosis","volume":"23","author":"Turco","year":"2019","journal-title":"Clin. 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