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Sphingosine\u2010l\u2010phosphate (S1P), derived from the vascular endothelium, is a significant regulator of blood pressure. However, the mechanisms underlying the regulation of S1P biosynthetic pathways in arteries remain to be further clarified. Here, we reported that Reticulon 3 (RTN3) regulated endothelial sphingolipid biosynthesis and blood pressure. We employed public datasets, patients, and mouse models to explore the pathophysiological roles of RTN3 in blood pressure control. The underlying mechanisms were studied in human umbilical vein endothelial cells (HUVECs). We reported that increased RTN3 was found in patients and that RTN3\u2010null mice presented hypotension. In HUVECs, RTN3 can regulate migration and tube formation via the S1P signaling pathway. Mechanistically, RTN3 can interact with CERS2 to promote the selective autophagy of CERS2 and further influence S1P signals to control blood pressure. We also identified an <jats:italic>RTN3<\/jats:italic> variant (c.116C&gt;T, p.T39M) in a family with hypertension. Our data provided the first evidence of the association between RTN3 level changes and blood pressure anomalies and preliminarily elucidated the importance of RTN3 in S1P metabolism and blood pressure regulation.<\/jats:p>","DOI":"10.1002\/mco2.480","type":"journal-article","created":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T18:18:42Z","timestamp":1707848322000},"source":"Crossref","is-referenced-by-count":3,"title":["Reticulon 3 regulates sphingosine\u20101\u2010phosphate synthesis in endothelial cells to control blood pressure"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3140-2216","authenticated-orcid":false,"given":"Jie\u2010Yuan","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Orthopaedics Microsurgery &amp; Reconstruction Research Center Xiangya Hospital Central South University  Changsha China"},{"name":"Department of Cell Biology, School of Life Sciences Central South University Changsha 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