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Sphingosine 1\u2010phosphate (S1P) tightly regulates vascular homeostasis via its receptor, S1pr1. We therefore hypothesize that endothelial S1pr1 might be involved in pathological cardiac remodelling. In this study, heart failure was induced by transverse aortic constriction (TAC) operation. S1pr1 expression is significantly increased in microvascular endothelial cells (ECs) of post\u2010TAC hearts. Endothelial\u2010specific deletion of\n                    <jats:italic>S1pr1<\/jats:italic>\n                    significantly aggravated cardiac dysfunction and deteriorated cardiac hypertrophy and fibrosis in myocardium. In vitro experiments demonstrated that S1P\/S1pr1 praxis activated AKT\/eNOS signalling pathway, leading to more production of nitric oxide (NO), which is an essential cardiac protective factor. Inhibition of AKT\/eNOS pathway reversed the inhibitory effect of EC\u2010S1pr1\u2010overexpression on angiotensin II (AngII)\u2010induced cardiomyocyte (CM) hypertrophy, as well as on TGF\u2010\u03b2\u2010mediated cardiac fibroblast proliferation and transformation towards myofibroblasts. Finally, pharmacological activation of S1pr1 ameliorated TAC\u2010induced cardiac hypertrophy and fibrosis, leading to an improvement in cardiac function. Together, our results suggest that EC\u2010S1pr1 might prevent the development of pressure overload\u2010induced heart failure via AKT\/eNOS pathway, and thus pharmacological activation of S1pr1 or EC\u2010targeting S1pr1\u2010AKT\u2010eNOS pathway could provide a future novel therapy to improve cardiac function during heart failure development.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.14900","type":"journal-article","created":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T05:37:48Z","timestamp":1576733868000},"page":"2013-2026","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Endothelial S1pr1 regulates pressure overload\u2010induced cardiac remodelling through AKT\u2010eNOS pathway"],"prefix":"10.1111","volume":"24","author":[{"given":"Xiuxiang","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Arrhythmias of the Ministry of Education of China Research Center for 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