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U.S.A."],"published-print":{"date-parts":[[2020,5,26]]},"abstract":"<jats:p>Endothelial cell nitric oxide (NO) synthase (eNOS), the enzyme responsible for synthesis of NO in endothelial cells, is regulated by complex posttranslational mechanisms. Sinusoidal portal hypertension, a disorder characterized by liver sinusoidal endothelial cell (SEC) injury with resultant reduced eNOS activity and NO production within the liver, has been associated with defects in eNOS protein\u2013protein interactions and posttranslational modifications. We and others have previously identified novel eNOS interactors, including G protein-coupled receptor (GPCR) kinase interactor 1 (GIT1), which we found to play an unexpected stimulatory role in GPCR-mediated eNOS signaling. Here we report that \u03b2-arrestin 2 (\u03b2-Arr2), a canonical GPCR signaling partner, localizes in SECs with eNOS in a GIT1\/eNOS\/NO signaling module. Most importantly, we show that \u03b2-Arr2 stimulates eNOS activity, and that \u03b2-Arr2 expression is reduced and formation of the GIT1\/eNOS\/NO signaling module is interrupted during liver injury. In \u03b2-Arr2\u2013deficient mice, bile duct ligation injury (BDL) led to significantly reduced eNOS activity and to a dramatic increase in portal hypertension compared to BDL in wild-type mice. Overexpression of \u03b2-Arr2 in injured or \u03b2-Arr2\u2013deficient SECs rescued eNOS function by increasing eNOS complex formation and NO production. We also found that \u03b2-Arr2\u2013mediated GIT1\/eNOS complex formation is dependent on Erk1\/2 and Src, two kinases known to interact with and be activated by \u03b2-Arr2 in response to GCPR activation. Our data emphasize that \u03b2-Arr2 is an integral component of the GIT1\/eNOS\/NO signaling pathway and have implications for the pathogenesis of sinusoidal portal hypertension.<\/jats:p>","DOI":"10.1073\/pnas.1922608117","type":"journal-article","created":{"date-parts":[[2020,5,13]],"date-time":"2020-05-13T20:12:54Z","timestamp":1589400774000},"page":"11483-11492","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":30,"title":["\u03b2-Arrestin2 is a critical component of the GPCR\u2013eNOS signalosome"],"prefix":"10.1073","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9850-6437","authenticated-orcid":false,"given":"Songling","family":"Liu","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC 29425;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2805-6949","authenticated-orcid":false,"given":"Louis M.","family":"Luttrell","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC 29425;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8053-5026","authenticated-orcid":false,"given":"Richard T.","family":"Premont","sequence":"additional","affiliation":[{"name":"Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106;"},{"name":"Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don C.","family":"Rockey","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC 29425;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,5,13]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-018-0097-3"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.05.047"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.07.009"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0676.2000.020001003.x"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.2174\/13816128113196660745"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M306930200"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1289"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.320465"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.115.3.455"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.24.8879"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5402.655"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.23777"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1067\/mva.2000.107989"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2001.281.1.H22"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0092926"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000769"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45194"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.05.012"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.05.024"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.113.211854"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1729"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M507460200"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2016.11.017"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.521203"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tice.2015.12.006"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00512.2000"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1211"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1364\/OE.17.008264"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M065326"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471143030.cb0419s62"},{"key":"e_1_3_4_31_2","first-page":"e51955","article-title":"Monitoring of systemic and hepatic hemodynamic parameters in mice","volume":"4","author":"Xie C.","year":"2014","unstructured":"C. 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