{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T17:53:08Z","timestamp":1780941188482,"version":"3.54.1"},"reference-count":69,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2019,12,17]],"date-time":"2019-12-17T00:00:00Z","timestamp":1576540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hungarian National Research, Development and Innovation Office","award":["K-101775, K-112964, K-125174 and NVKP_16-1-2016-0042"],"award-info":[{"award-number":["K-101775, K-112964, K-125174 and NVKP_16-1-2016-0042"]}]},{"name":"Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the Molecular Biology thematic program of the Semmelweis Univers","award":["EFOP-3.6.3-VEKOP-16-2017-00009"],"award-info":[{"award-number":["EFOP-3.6.3-VEKOP-16-2017-00009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sphingosine-1-phosphate (S1P) has been implicated recently in the physiology and pathology of the cardiovascular system including regulation of vascular tone. Pilot experiments showed that the vasoconstrictor effect of S1P was enhanced markedly in the presence of phenylephrine (PE). Based on this observation, we hypothesized that S1P might modulate \u03b11-adrenergic vasoactivity. In murine aortas, a 20-minute exposure to S1P but not to its vehicle increased the Emax and decreased the EC50 of PE-induced contractions indicating a hyperreactivity to \u03b11-adrenergic stimulation. The potentiating effect of S1P disappeared in S1P2 but not in S1P3 receptor-deficient vessels. In addition, smooth muscle specific conditional deletion of G12\/13 proteins or pharmacological inhibition of the Rho-associated protein kinase (ROCK) by Y-27632 or fasudil abolished the effect of S1P on \u03b11-adrenergic vasoconstriction. Unexpectedly, PE-induced contractions remained enhanced markedly as late as three hours after S1P-exposure in wild-type (WT) and S1P3 KO but not in S1P2 KO vessels. In conclusion, the S1P\u2013S1P2\u2013G12\/13\u2013ROCK signaling pathway appears to have a major influence on \u03b11-adrenergic vasoactivity. This cooperativity might lead to sustained vasoconstriction when increased sympathetic tone is accompanied by increased S1P production as it occurs during acute coronary syndrome and stroke.<\/jats:p>","DOI":"10.3390\/ijms20246361","type":"journal-article","created":{"date-parts":[[2019,12,20]],"date-time":"2019-12-20T03:19:36Z","timestamp":1576811976000},"page":"6361","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Sphingosine-1-Phosphate Enhances \u03b11-Adrenergic Vasoconstriction via S1P2\u2013G12\/13\u2013ROCK Mediated Signaling"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4162-0882","authenticated-orcid":false,"given":"Cec\u00edlia R.","family":"Panta","sequence":"first","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9va","family":"Ruisanchez","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorottya","family":"M\u00f3r\u00e9","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter T.","family":"Dancs","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Balogh","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1gnes","family":"F\u00fcl\u00f6p","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margit","family":"Ker\u00e9k","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0456-1270","authenticated-orcid":false,"given":"Richard L.","family":"Proia","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Offermanns","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor J.","family":"Tigyi","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"},{"name":"Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6015-0359","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Beny\u00f3","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.bbalip.2008.07.001","article-title":"Sphingosine-1-phosphate regulation of mammalian development","volume":"1781","author":"Kono","year":"2008","journal-title":"Biochim. 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