{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T22:46:45Z","timestamp":1778885205644,"version":"3.51.4"},"reference-count":24,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2014,7,5]],"date-time":"2014-07-05T00:00:00Z","timestamp":1404518400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH","award":["R01 DK 57830"],"award-info":[{"award-number":["R01 DK 57830"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2015,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background &amp; Aims<\/jats:title><jats:p>Portal hypertension results from endothelial dysfunction after liver injury caused in part by abnormal production of endothelial cell derived nitric oxide synthase (eNOS). Here, we have postulated that endothelial mechanosensing pathways involving integrin\u2010linked kinase (ILK) may play a critical role in portal hypertension, eNOS expression and function. In this study, we investigated the role of ILK and the small GTP\u2010binding protein, Rho, in sinusoidal endothelial cell (SEC) eNOS regulation and function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Primary liver <jats:styled-content style=\"fixed-case\">SEC<\/jats:styled-content>s were isolated using standard techniques. Liver injury was induced by performing bile duct ligation (<jats:styled-content style=\"fixed-case\">BDL<\/jats:styled-content>). To examine the expression of Rho and <jats:styled-content style=\"fixed-case\">ILK <\/jats:styled-content><jats:italic>in vivo<\/jats:italic> during wound healing, <jats:styled-content style=\"fixed-case\">SEC<\/jats:styled-content>s were infected with constitutively active Rho (V14), a dominant negative Rho (N19) and constructs encoding <jats:styled-content style=\"fixed-case\">ILK<\/jats:styled-content> and a short hairpin\u2010inhibiting <jats:styled-content style=\"fixed-case\">ILK<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Integrin\u2010linked kinase expression was increased in SECs after liver injury; endothelin\u20101, vascular endothelial growth factor, and transforming growth factor beta\u20101 stimulated ILK expression in SECs. ILK expression in turn led to eNOS upregulation and to enhance eNOS phosphorylation and NO production. ILK knockdown or ILK (kinase) inhibition reduced eNOS mRNA expression, promoter activity, eNOS expression and ultimately NO production. In contrast, ILK overexpression had the opposite effect. Inhibition of ILK activity also disrupted the actin cytoskeleton in isolated SECs. Rho overexpression suppressed phosphorylation of the serine\u2010threonine kinase, Akt and inhibited eNOS phosphorylation. Finally, inhibition of Rho function with the RGS domain of the p115\u2010Rho\u2010specific GEF (p115\u2010RGS) significantly increased eNOS phosphorylation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data suggest a potential role for ILK, the cytoskeleton and ILK signalling partners including Rho in regulating intrahepatic SEC eNOS expression and function.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.12606","type":"journal-article","created":{"date-parts":[[2014,6,6]],"date-time":"2014-06-06T10:36:46Z","timestamp":1402051006000},"page":"1213-1221","source":"Crossref","is-referenced-by-count":14,"title":["Integrin\u2010linked kinase regulates endothelial cell nitric oxide synthase expression in hepatic sinusoidal endothelial cells"],"prefix":"10.1111","volume":"35","author":[{"given":"Mahnoush S.","family":"Shafiei","sequence":"first","affiliation":[{"name":"Division of Digestive and Liver Diseases University of Texas Southwestern Medical Center Dallas TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songling","family":"Lui","sequence":"additional","affiliation":[{"name":"The Department of Medicine The Medical University of South Carolina Charleston SC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Don C.","family":"Rockey","sequence":"additional","affiliation":[{"name":"The Department of Medicine The Medical University of South Carolina Charleston SC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,7,5]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408217102"},{"issue":"3","key":"e_1_2_7_3_1","first-page":"S48","article-title":"Endothelial alterations in hypercholesterolemia: more than simply vasodilator dysfunction","volume":"32","author":"Tsao PS","year":"1998","journal-title":"J Cardiovasc 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