{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T13:44:53Z","timestamp":1792244693011,"version":"4.4.0"},"reference-count":114,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T00:00:00Z","timestamp":1683763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32171106"],"award-info":[{"award-number":["32171106"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022YFS0627"],"award-info":[{"award-number":["2022YFS0627"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022YFS0607"],"award-info":[{"award-number":["2022YFS0607"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022NSFSC0703"],"award-info":[{"award-number":["2022NSFSC0703"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2020ZRZD012"],"award-info":[{"award-number":["2020ZRZD012"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sichuan Science and Technology Program","award":["32171106"],"award-info":[{"award-number":["32171106"]}]},{"name":"Sichuan Science and Technology Program","award":["2022YFS0627"],"award-info":[{"award-number":["2022YFS0627"]}]},{"name":"Sichuan Science and Technology Program","award":["2022YFS0607"],"award-info":[{"award-number":["2022YFS0607"]}]},{"name":"Sichuan Science and Technology Program","award":["2022NSFSC0703"],"award-info":[{"award-number":["2022NSFSC0703"]}]},{"name":"Sichuan Science and Technology Program","award":["2020ZRZD012"],"award-info":[{"award-number":["2020ZRZD012"]}]},{"name":"Natural Science Foundation of Sichuan Province","award":["32171106"],"award-info":[{"award-number":["32171106"]}]},{"name":"Natural Science Foundation of Sichuan Province","award":["2022YFS0627"],"award-info":[{"award-number":["2022YFS0627"]}]},{"name":"Natural Science Foundation of Sichuan Province","award":["2022YFS0607"],"award-info":[{"award-number":["2022YFS0607"]}]},{"name":"Natural Science Foundation of Sichuan Province","award":["2022NSFSC0703"],"award-info":[{"award-number":["2022NSFSC0703"]}]},{"name":"Natural Science Foundation of Sichuan Province","award":["2020ZRZD012"],"award-info":[{"award-number":["2020ZRZD012"]}]},{"name":"Southwest Medical University","award":["32171106"],"award-info":[{"award-number":["32171106"]}]},{"name":"Southwest Medical University","award":["2022YFS0627"],"award-info":[{"award-number":["2022YFS0627"]}]},{"name":"Southwest Medical University","award":["2022YFS0607"],"award-info":[{"award-number":["2022YFS0607"]}]},{"name":"Southwest Medical University","award":["2022NSFSC0703"],"award-info":[{"award-number":["2022NSFSC0703"]}]},{"name":"Southwest Medical University","award":["2020ZRZD012"],"award-info":[{"award-number":["2020ZRZD012"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Sphingosine-1-phosphate (S1P) is an important sphingolipid molecule involved in regulating cardiovascular functions in physiological and pathological conditions by binding and activating the three G protein-coupled receptors (S1PR1, S1PR2, and S1PR3) expressed in endothelial and smooth muscle cells, as well as cardiomyocytes and fibroblasts. It exerts its actions through various downstream signaling pathways mediating cell proliferation, migration, differentiation, and apoptosis. S1P is essential for the development of the cardiovascular system, and abnormal S1P content in the circulation is involved in the pathogenesis of cardiovascular disorders. This article reviews the effects of S1P on cardiovascular function and signaling mechanisms in different cell types in the heart and blood vessels under diseased conditions. Finally, we look forward to more clinical findings with approved S1PR modulators and the development of S1P-based therapies for cardiovascular diseases.<\/jats:p>","DOI":"10.3390\/biom13050818","type":"journal-article","created":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T02:36:59Z","timestamp":1683859019000},"page":"818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Sphingosine-1-Phosphate Signaling in Cardiovascular Diseases"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7433-8725","authenticated-orcid":false,"given":"Na","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Yi","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zeng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui-Lan","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1515\/bchm2.1968.349.2.1745","article-title":"Metabolism of sphingosine bases. Ix. Degradation in vitro of dihydrospingosine and dihydrospingosine phosphate to palmitaldehyde and ethanolamine phosphate","volume":"349","author":"Stoffel","year":"1968","journal-title":"Hoppe Seylers Z. Physiol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0090-6980(01)00103-4","article-title":"Sphingosine 1-phosphate: Synthesis and release","volume":"64","author":"Yatomi","year":"2001","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1007\/s40265-021-01528-8","article-title":"Targeting sphingosine-1-phosphate signaling in immune-mediated diseases: Beyond multiple sclerosis","volume":"81","year":"2021","journal-title":"Drugs"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/nature13475","article-title":"Sphingolipid metabolites in inflammatory disease","volume":"510","author":"Maceyka","year":"2014","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/onc.2011.267","article-title":"Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy","volume":"31","author":"Spiegel","year":"2012","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4806541","DOI":"10.1155\/2017\/4806541","article-title":"The role of sphingosine-1-phosphate and ceramide-1-phosphate in inflammation and cancer","volume":"2017","author":"Hait","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.diabet.2019.07.006","article-title":"Associations between specific plasma ceramides and severity of coronary-artery stenosis assessed by coronary angiography","volume":"46","author":"Mantovani","year":"2020","journal-title":"Diabetes Metab."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Spijkers, L.J., van den Akker, R.F., Janssen, B.J., Debets, J.J., De Mey, J.G., Stroes, E.S., van den Born, B.J., Wijesinghe, D.S., Chalfant, C.E., and MacAleese, L. (2011). Hypertension is associated with marked alterations in sphingolipid biology: A potential role for ceramide. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021817"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.2741\/4458","article-title":"Implication of sphingosin-1-phosphate in cardiovascular regulation","volume":"21","author":"Li","year":"2016","journal-title":"Front. Biosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.atherosclerosis.2016.12.009","article-title":"High density lipoprotein (hdl)-associated sphingosine 1-phosphate (s1p) inhibits macrophage apoptosis by stimulating stat3 activity and survivin expression","volume":"257","author":"Feuerborn","year":"2017","journal-title":"Atherosclerosis"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1080\/09513590.2017.1290072","article-title":"Sphingosine-1-phosphate activates the akt pathway to inhibit chemotherapy induced human granulosa cell apoptosis","volume":"33","author":"Li","year":"2017","journal-title":"Gynecol. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1042\/BJ20060251","article-title":"Extracellular export of sphingosine kinase-1a contributes to the vascular s1p gradient","volume":"397","author":"Venkataraman","year":"2006","journal-title":"Biochem. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e00219","DOI":"10.1016\/j.heliyon.2016.e00219","article-title":"Sphingosine-1-phosphate in the lymphatic fluid determined by novel methods","volume":"2","author":"Nagahashi","year":"2016","journal-title":"Heliyon"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1002\/jcb.20097","article-title":"Generation and metabolism of bioactive sphingosine-1-phosphate","volume":"92","author":"Milstien","year":"2004","journal-title":"J. Cell. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Tolksdorf, C., Moritz, E., Wolf, R., Meyer, U., Marx, S., Bien-Moller, S., Garscha, U., Jedlitschky, G., and Rauch, B.H. (2022). Platelet-derived s1p and its relevance for the communication with immune cells in multiple human diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810278"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1161\/CIRCRESAHA.107.165845","article-title":"Vascular endothelium as a contributor of plasma sphingosine 1-phosphate","volume":"102","author":"Venkataraman","year":"2008","journal-title":"Circ. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1194\/jlr.R059543","article-title":"Sources, metabolism, and regulation of circulating sphingosine-1-phosphate","volume":"56","author":"Chabowski","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hisano, Y., Kobayashi, N., Yamaguchi, A., and Nishi, T. (2012). Mouse spns2 functions as a sphingosine-1-phosphate transporter in vascular endothelial cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038941"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.celrep.2012.09.021","article-title":"The transporter spns2 is required for secretion of lymph but not plasma sphingosine-1-phosphate","volume":"2","author":"Mendoza","year":"2012","journal-title":"Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/nature24053","article-title":"Mfsd2b is essential for the sphingosine-1-phosphate export in erythrocytes and platelets","volume":"550","author":"Vu","year":"2017","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10477","DOI":"10.1074\/jbc.M109.064162","article-title":"Estradiol induces export of sphingosine 1-phosphate from breast cancer cells via abcc1 and abcg2","volume":"285","author":"Takabe","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1160\/TH17-04-0291","article-title":"Release of platelet-derived sphingosine-1-phosphate involves multidrug resistance protein 4 (mrp4\/abcc4) and is inhibited by statins","volume":"118","author":"Vogt","year":"2018","journal-title":"Thromb. Haemost."},{"key":"ref_23","first-page":"8","article-title":"Sphingosine-1-phosphate and lipid phosphohydrolases","volume":"1582","author":"Peterson","year":"2002","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Lipids"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1124\/jpet.116.235002","article-title":"Sphingosine-1-phosphate (s1p) lyase inhibition causes increased cardiac s1p levels and bradycardia in rats","volume":"359","author":"Harris","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5055","DOI":"10.1128\/MCB.02107-05","article-title":"Sphingosine-1-phosphate phosphohydrolase regulates endoplasmic reticulum-to-golgi trafficking of ceramide","volume":"26","author":"Giussani","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1042\/BST0331370","article-title":"Lipid phosphate phosphatases and lipid phosphate signalling","volume":"33","author":"Pyne","year":"2005","journal-title":"Biochem. Soc. Trans."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.cellsig.2008.08.008","article-title":"Role of sphingosine kinases and lipid phosphate phosphatases in regulating spatial sphingosine 1-phosphate signalling in health and disease","volume":"21","author":"Pyne","year":"2009","journal-title":"Cell. Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s40265-020-01431-8","article-title":"Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: Differential downstream receptor signalling and clinical profile effects","volume":"81","author":"Chun","year":"2021","journal-title":"Drugs"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.jgg.2015.08.006","article-title":"Galphas relays sphingosine-1-phosphate receptor 1 signaling to stabilize vascular endothelial-cadherin at endothelial junctions to control mouse embryonic vascular integrity","volume":"42","author":"Shao","year":"2015","journal-title":"J. Genet. Genom."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"H736","DOI":"10.1152\/ajpheart.00316.2007","article-title":"Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes","volume":"294","author":"Landeen","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11954","DOI":"10.1074\/jbc.M707422200","article-title":"S1p1 receptor localization confers selectivity for gi-mediated camp and contractile responses","volume":"283","author":"Means","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e2117716119","DOI":"10.1073\/pnas.2117716119","article-title":"Structural insights into sphingosine-1-phosphate receptor activation","volume":"119","author":"Yu","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/s41589-021-00930-3","article-title":"Structural basis of sphingosine-1-phosphate receptor 1 activation and biased agonism","volume":"18","author":"Xu","year":"2022","journal-title":"Nat. Chem. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/s41467-022-28417-2","article-title":"Differential activation mechanisms of lipid gpcrs by lysophosphatidic acid and sphingosine 1-phosphate","volume":"13","author":"Liu","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"eabn0067","DOI":"10.1126\/sciadv.abn0067","article-title":"Structure of s1pr2\u2013heterotrimeric g13 complex","volume":"8","author":"Chen","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"eabf5325","DOI":"10.1126\/sciadv.abf5325","article-title":"Endogenous agonist\u2013bound s1pr3 structure reveals determinants of g protein\u2013subtype bias","volume":"7","author":"Maeda","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1038\/s41422-021-00566-x","article-title":"Structures of signaling complexes of lipid receptors s1pr1 and s1pr5 reveal mechanisms of activation and drug recognition","volume":"31","author":"Yuan","year":"2021","journal-title":"Cell Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4736","DOI":"10.1038\/s41467-022-32447-1","article-title":"Structural basis for receptor selectivity and inverse agonism in s1p5 receptors","volume":"13","author":"Lyapina","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_39","first-page":"213","article-title":"Sphingosine 1-phosphate and its regulatory role in vascular endothelial cells","volume":"37","author":"Qiu","year":"2022","journal-title":"Histol. Histopathol."},{"key":"ref_40","first-page":"158760","article-title":"Post-translational modifications of s1pr1 and endothelial barrier regulation","volume":"1865","author":"Anwar","year":"2020","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell. Biol. Lipids"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.prp.2011.11.008","article-title":"Lps and tnf-alpha induce expression of sphingosine-1-phosphate receptor-2 in human microvascular endothelial cells","volume":"208","author":"Du","year":"2012","journal-title":"Pathol. Res. Pract."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1161\/CIRCRESAHA.120.318412","article-title":"Programming to s1pr1(+) endothelial cells promotes restoration of vascular integrity","volume":"129","author":"Akhter","year":"2021","journal-title":"Circ. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1097\/SHK.0000000000000814","article-title":"Sphingosine-1-phosphate: A potential biomarker and therapeutic target for endothelial dysfunction and sepsis?","volume":"47","author":"Winkler","year":"2017","journal-title":"Shock"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/j.bbrc.2017.06.189","article-title":"S1pr2 antagonist protects endothelial cells against high glucose-induced mitochondrial apoptosis through the akt\/gsk-3\u03b2 signaling pathway","volume":"490","author":"Liu","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1165\/rcmb.2012-0048OC","article-title":"Sphingosine-1-phosphate receptor-3 is a novel biomarker in acute lung injury","volume":"47","author":"Sun","year":"2012","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"H363","DOI":"10.1152\/ajpheart.00687.2013","article-title":"Sphingosine-1-phosphate protects endothelial glycocalyx by inhibiting syndecan-1 shedding","volume":"306","author":"Zeng","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.yexcr.2015.08.013","article-title":"Sphingosine 1-phosphate induced synthesis of glycocalyx on endothelial cells","volume":"339","author":"Zeng","year":"2015","journal-title":"Exp. Cell Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/micc.12278","article-title":"Sphingosine-1-phosphate maintains normal vascular permeability by preserving endothelial surface glycocalyx in intact microvessels","volume":"23","author":"Zhang","year":"2016","journal-title":"Microcirculation"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Mensah, S.A., Cheng, M.J., Homayoni, H., Plouffe, B.D., Coury, A.J., and Ebong, E.E. (2017). Regeneration of glycocalyx by heparan sulfate and sphingosine 1-phosphate restores inter-endothelial communication. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186116"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1097\/SHK.0000000000001280","article-title":"Sphingosine-1-phosphate reduces hemorrhagic shock and resuscitation-induced microvascular leakage by protecting endothelial mitochondrial integrity","volume":"52","author":"Alves","year":"2019","journal-title":"Shock"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1097\/TA.0000000000002446","article-title":"Protective effects of plasma products on the endothelial-glycocalyx barrier following trauma-hemorrhagic shock: Is sphingosine-1 phosphate responsible?","volume":"87","author":"Diebel","year":"2019","journal-title":"J. Trauma. Acute Care Surg."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.devcel.2012.08.005","article-title":"The sphingosine-1-phosphate receptor s1pr1 restricts sprouting angiogenesis by regulating the interplay between ve-cadherin and vegfr2","volume":"23","author":"Gaengel","year":"2012","journal-title":"Dev. Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3472","DOI":"10.1016\/j.celrep.2019.11.036","article-title":"Sphingosine-1-phosphate receptor 1 activity promotes tumor growth by amplifying vegf-vegfr2 angiogenic signaling","volume":"29","author":"Anwar","year":"2019","journal-title":"Cell Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s10456-018-9603-z","article-title":"High-density lipoprotein (hdl) promotes angiogenesis via s1p3-dependent vegfr2 activation","volume":"21","author":"Jin","year":"2018","journal-title":"Angiogenesis"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"eaay8627","DOI":"10.1126\/sciadv.aay8627","article-title":"Mfsd2a and spns2 are essential for sphingosine-1-phosphate transport in the formation and maintenance of the blood-brain barrier","volume":"6","author":"Wang","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Jeya Paul, J., Weigel, C., M\u00fcller, T., Heller, R., Spiegel, S., and Gr\u00e4ler, M.H. (2020). Inflammatory conditions disrupt constitutive endothelial cell barrier stabilization by alleviating autonomous secretion of sphingosine 1-phosphate. Cells, 9.","DOI":"10.3390\/cells9040928"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1093\/cvr\/cvp064","article-title":"Sphingosine-1-phosphate and modulation of vascular tone","volume":"82","author":"Igarashi","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.taap.2018.03.032","article-title":"Angiotensin ii facilitates neointimal formation by increasing vascular smooth muscle cell migration: Involvement of ape\/ref-1-mediated overexpression of sphingosine-1-phosphate receptor 1","volume":"347","author":"Lee","year":"2018","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"106874","DOI":"10.1016\/j.vph.2021.106874","article-title":"Sphingosine 1-phosphate-induced nitric oxide production simultaneously controls endothelial barrier function and vascular tone in resistance arteries","volume":"140","author":"Kerage","year":"2021","journal-title":"Vasc. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"104793","DOI":"10.1016\/j.phrs.2020.104793","article-title":"Significance of sphingosine-1-phosphate in cardiovascular physiology and pathology","volume":"156","author":"Jozefczuk","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_61","first-page":"2267","article-title":"Sphingosine-1-phosphate-induced release of timp-2 from vascular smooth muscle cells inhibits angiogenesis","volume":"125","author":"Mascall","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"F35","DOI":"10.1152\/ajprenal.00014.2011","article-title":"A novel lipid natriuretic factor in the renal medulla: Sphingosine-1-phosphate","volume":"301","author":"Zhu","year":"2011","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.pharmthera.2017.11.001","article-title":"The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives","volume":"185","author":"Huwiler","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1161\/HYPERTENSIONAHA.117.09088","article-title":"S1pr1 (sphingosine-1-phosphate receptor 1) signaling regulates blood flow and pressure","volume":"70","author":"Cantalupo","year":"2017","journal-title":"Hypertension"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1073\/pnas.1516485113","article-title":"T cell-intrinsic s1pr1 regulates endogenous effector t-cell egress dynamics from lymph nodes during infection","volume":"113","author":"Benechet","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1093\/cvr\/cvp086","article-title":"Sphingosine-1-phosphate receptor signalling in the heart","volume":"82","author":"Means","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e003393","DOI":"10.1161\/JAHA.116.003393","article-title":"Sphingosine-1-phosphate receptor 1 regulates cardiac function by modulating Ca2+ sensitivity and Na+\/H+ exchange and mediates protection by ischemic preconditioning","volume":"5","author":"Keul","year":"2016","journal-title":"J. Am. Heart Assoc."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"930615","DOI":"10.3389\/fphar.2022.930615","article-title":"Dose-dependent reduction of lymphocyte count and heart rate after multiple administration of lc51-0255, a novel sphingosine-1-phosphate receptor 1 modulator, in healthy subjects","volume":"13","author":"Hwang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"17562864221133163","DOI":"10.1177\/17562864221133163","article-title":"S1p receptor modulators and the cardiovascular autonomic nervous system in multiple sclerosis: A narrative review","volume":"15","author":"Constantinescu","year":"2022","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1007\/s004240051088","article-title":"Effects of sphingosine 1-phosphate on pacemaker activity in rabbit sino-atrial node cells","volume":"438","author":"Guo","year":"1999","journal-title":"Pflug. Arch."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1093\/cvr\/cvu136","article-title":"Atheroprotective role of high-density lipoprotein (hdl)-associated sphingosine-1-phosphate (s1p)","volume":"103","author":"Simoni","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1096\/fj.201801245R","article-title":"Potent anti-inflammatory properties of hdl in vascular smooth muscle cells mediated by hdl-s1p and their impairment in coronary artery disease due to lower hdl-s1p: A new aspect of hdl dysfunction and its therapy","volume":"33","author":"Keul","year":"2019","journal-title":"FASEB J."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Gonzalez, L., Qian, A.S., Tahir, U., Yu, P., and Trigatti, B.L. (2017). Sphingosine-1-phosphate receptor 1, expressed in myeloid cells, slows diet-induced atherosclerosis and protects against macrophage apoptosis in ldlr ko mice. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122721"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.atherosclerosis.2015.03.020","article-title":"Ski-II\u2014A sphingosine kinase 1 inhibitor\u2014Exacerbates atherosclerosis in low-density lipoprotein receptor-deficient (ldl-r\u2212\/\u2212) mice on high cholesterol diet","volume":"240","author":"Ceglarek","year":"2015","journal-title":"Atherosclerosis"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Bot, M., Van Veldhoven, P.P., de Jager, S.C., Johnson, J., Nijstad, N., Van Santbrink, P.J., Westra, M.M., Van Der Hoeven, G., Gijbels, M.J., and M\u00fcller-Tidow, C. (2013). Hematopoietic sphingosine 1-phosphate lyase deficiency decreases atherosclerotic lesion development in ldl-receptor deficient mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063360"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1007\/s00395-010-0112-5","article-title":"Sphingosine 1-phosphate levels in plasma and hdl are altered in coronary artery disease","volume":"105","author":"Sattler","year":"2010","journal-title":"Basic Res. Cardiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1016\/j.jacc.2015.07.057","article-title":"Defects of high-density lipoproteins in coronary artery disease caused by low sphingosine-1-phosphate content: Correction by sphingosine-1-phosphate-loading","volume":"66","author":"Sattler","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1007\/s00210-015-1159-5","article-title":"Fty720 and two novel butterfly derivatives exert a general anti-inflammatory potential by reducing immune cell adhesion to endothelial cells through activation of s1p3 and phosphoinositide 3-kinase","volume":"388","author":"Imeri","year":"2015","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"16","DOI":"10.5551\/jat.RV17010","article-title":"Sphingosine 1-phosphate and atherosclerosis","volume":"25","author":"Kurano","year":"2018","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1097\/MOL.0000000000000825","article-title":"Sphingosine-1-phosphate: Metabolism, transport, atheroprotection and effect of statin treatment","volume":"33","author":"Therond","year":"2022","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s10456-019-09689-7","article-title":"Role of melatonin in controlling angiogenesis under physiological and pathological conditions","volume":"23","author":"Ma","year":"2020","journal-title":"Angiogenesis"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1038\/s41419-022-05210-z","article-title":"S1pr1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression","volume":"13","author":"Wang","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1158\/0008-5472.CAN-05-2001","article-title":"Antagonism of sphingosine-1-phosphate receptors by fty720 inhibits angiogenesis and tumor vascularization","volume":"66","author":"LaMontagne","year":"2006","journal-title":"Cancer Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5172","DOI":"10.7150\/thno.71585","article-title":"Endothelial s1pr2 regulates post-ischemic angiogenesis via akt\/enos signaling pathway","volume":"12","author":"Zhou","year":"2022","journal-title":"Theranostics"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/978-1-0716-2966-6_20","article-title":"Angiogenesis model of cornea to understand the role of sphingosine 1-phosphate","volume":"2625","author":"Wilkerson","year":"2023","journal-title":"Methods Mol. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1210\/me.2014-1388","article-title":"Inhibition of sphingosine kinase 1 ameliorates angiotensin ii-induced hypertension and inhibits transmembrane calcium entry via store-operated calcium channel","volume":"29","author":"Wilson","year":"2015","journal-title":"Mol. Endocrinol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1161\/ATVBAHA.122.318820","article-title":"Endothelial k(ca)3.1 and k(ca)2.3 mediate s1p (sphingosine-1-phosphate)-dependent vasodilation and blood pressure homeostasis","volume":"43","author":"Li","year":"2023","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1530\/JOE-16-0550","article-title":"Obesity-stimulated aldosterone release is not related to an s1p-dependent mechanism","volume":"235","author":"Werth","year":"2017","journal-title":"J. Endocrinol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"eaal2722","DOI":"10.1126\/scisignal.aal2722","article-title":"An engineered s1p chaperone attenuates hypertension and ischemic injury","volume":"10","author":"Swendeman","year":"2017","journal-title":"Sci. Signal."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"S86","DOI":"10.1016\/j.placenta.2013.12.006","article-title":"Review: Novel insights into the regulation of vascular tone by sphingosine 1-phosphate","volume":"35","author":"Kerage","year":"2014","journal-title":"Placenta"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.coph.2008.11.002","article-title":"Targeting sphingosine-1-phosphate signalling for cardioprotection","volume":"9","author":"Kennedy","year":"2009","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1161\/CIRCULATIONAHA.105.607135","article-title":"High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia\/reperfusion injury in vivo via the s1p3 lysophospholipid receptor","volume":"114","author":"Theilmeier","year":"2006","journal-title":"Circulation"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1161\/CIRCRESAHA.120.316711","article-title":"Endothelial s1p1 signaling counteracts infarct expansion in ischemic stroke","volume":"128","author":"Nitzsche","year":"2021","journal-title":"Circ. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yjmcc.2016.12.008","article-title":"Selective coupling of the s1p3 receptor subtype to s1p-mediated rhoa activation and cardioprotection","volume":"103","author":"Yung","year":"2017","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.lfs.2018.01.023","article-title":"Sphingosine-1-phosphate (s1p) activates stat3 to protect against de novo acute heart failure (ahf)","volume":"196","author":"Deshpande","year":"2018","journal-title":"Life Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5985375","DOI":"10.1155\/2022\/5985375","article-title":"Inhibition of sphk1\/s1p signaling pathway alleviates fibrosis and inflammation of rat myocardium after myocardial infarction","volume":"2022","author":"Wu","year":"2022","journal-title":"Comput. Math. Methods Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1016\/j.jcmg.2021.01.027","article-title":"Multimodality imaging assessment of myocardial fibrosis","volume":"14","author":"Gupta","year":"2021","journal-title":"JACC Cardiovasc. Imaging"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1161\/CIRCULATIONAHA.113.002659","article-title":"\u03921-adrenergic receptor and sphingosine-1-phosphate receptor 1 (s1pr1) reciprocal downregulation influences cardiac hypertrophic response and progression to heart failure: Protective role of s1pr1 cardiac gene therapy","volume":"128","author":"Cannavo","year":"2013","journal-title":"Circulation"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Ohkura, S.I., Usui, S., Takashima, S.I., Takuwa, N., Yoshioka, K., Okamoto, Y., Inagaki, Y., Sugimoto, N., Kitano, T., and Takamura, M. (2017). Augmented sphingosine 1 phosphate receptor-1 signaling in cardiac fibroblasts induces cardiac hypertrophy and fibrosis through angiotensin ii and interleukin-6. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182329"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.lfs.2018.10.047","article-title":"Sphingosine 1-phosphate promotes mesenchymal stem cell-mediated cardioprotection against myocardial infarction via erk1\/2-mmp-9 and akt signaling axis","volume":"215","author":"Chen","year":"2018","journal-title":"Life Sci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"105564","DOI":"10.1016\/j.biocel.2019.105564","article-title":"Exosomes from adipose-derived mesenchymal stem cells ameliorate cardiac damage after myocardial infarction by activating s1p\/sk1\/s1pr1 signaling and promoting macrophage m2 polarization","volume":"114","author":"Deng","year":"2019","journal-title":"Int. J. Biochem. Cell. Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"10290","DOI":"10.1111\/jcmm.15744","article-title":"The role of sphingosine 1-phosphate and its receptors in cardiovascular diseases","volume":"24","author":"Ouyang","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_103","first-page":"303","article-title":"Sphingosine-1-phosphate and sphingosine kinase are critical for transforming growth factor-beta-stimulated collagen production by cardiac fibroblasts","volume":"82","author":"Swaney","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ccr.2006.02.023","article-title":"Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages","volume":"9","author":"Visentin","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1146\/annurev.pharmtox.40.1.459","article-title":"The role of rho in g protein-coupled receptor signal transduction","volume":"40","author":"Sah","year":"2000","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2234","DOI":"10.1161\/01.CIR.0000127939.16111.58","article-title":"Long-term inhibition of rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice","volume":"109","author":"Hattori","year":"2004","journal-title":"Circulation"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1161\/CIRCULATIONAHA.105.584623","article-title":"Decreased perivascular fibrosis but not cardiac hypertrophy in rock1+\/\u2212 haploinsufficient mice","volume":"112","author":"Rikitake","year":"2005","journal-title":"Circulation"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1006\/jmcc.2000.1129","article-title":"Induction of cardiac fibrosis by aldosterone","volume":"32","author":"Lijnen","year":"2000","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_109","first-page":"7664290","article-title":"Sphingosine 1-phosphate-upregulated cox-2\/pge(2) system contributes to human cardiac fibroblast apoptosis: Involvement of mmp-9-dependent transactivation of egfr cascade","volume":"2022","author":"Yang","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1093\/cvr\/cvaa046","article-title":"Vascular endothelial s1pr1 ameliorates adverse cardiac remodelling via stimulating reparative macrophage proliferation after myocardial infarction","volume":"117","author":"Kuang","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"872102","DOI":"10.3389\/fcvm.2022.872102","article-title":"Lymphatic endothelial sphingosine 1-phosphate receptor 1 enhances macrophage clearance via lymphatic system following myocardial infarction","volume":"9","author":"Li","year":"2022","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1093\/cvr\/cvp312","article-title":"S1p3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species","volume":"85","author":"Takuwa","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"281","DOI":"10.2353\/ajpath.2007.060485","article-title":"Immunomodulator fty720 induces myofibroblast differentiation via the lysophospholipid receptor s1p3 and smad3 signaling","volume":"170","author":"Keller","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.yjmcc.2017.07.004","article-title":"Plasma sphingosine-1-phosphate concentrations are associated with systolic heart failure in patients with ischemic heart disease","volume":"110","author":"Polzin","year":"2017","journal-title":"J. Mol. Cell. Cardiol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/5\/818\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:33:00Z","timestamp":1760124780000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/5\/818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,11]]},"references-count":114,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["biom13050818"],"URL":"https:\/\/doi.org\/10.3390\/biom13050818","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,11]]}}}