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Upon phosphate exposure, intricate signaling events orchestrate pro-calcific effects in the vasculature mediated by vascular smooth muscle cells (VSMCs). Sphingosine kinase 1 (SPHK1) produces sphingosine-1-phosphate (S1P) and is associated with complex effects in the vascular system. The present study investigated a possible involvement of SPHK1 in VSMC calcification. Experiments were performed in primary human aortic VSMCs under pro-calcific conditions, with pharmacological inhibition or knockdown of SPHK1 or SPNS2 (a lysolipid transporter involved in cellular S1P export), as well as in Sphk1-deficient and wild-type mice treated with cholecalciferol. In VSMCs, SPHK1 expression was up-regulated by pro-calcific conditions. Calcification medium up-regulated osteogenic marker mRNA expression and activity as well as calcification of VSMCs, effects significantly augmented by co-treatment with the SPHK1 inhibitor SK1-IN-1. SK1-IN-1 alone was sufficient to up-regulate osteogenic signaling in VSMCs during control conditions. Similarly, the SPHK1 inhibitor PF-543 and SPHK1 knockdown up-regulated osteogenic signaling in VSMCs and aggravated VSMC calcification. In contrast, co-treatment with the SPNS2 inhibitor SLF1081851 suppressed osteogenic signaling and calcification of VSMCs, effects abolished by silencing of SPHK1. In addition, Sphk1 deficiency aggravated vascular calcification and aortic osteogenic marker expression in mice after cholecalciferol overload. In conclusion, SPHK1 inhibition, knockdown, or deficiency aggravates vascular pro-calcific signaling and calcification. The reduced calcification after inhibition of S1P export suggests a possible involvement of intracellular S1P, but further studies are required to elucidate the complex roles of SPHKs and S1P signaling in calcifying VSMCs.<\/jats:p>","DOI":"10.1007\/s00424-025-03068-6","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T05:14:49Z","timestamp":1738559689000},"page":"815-826","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sphingosine kinase 1 inhibition aggravates vascular smooth muscle cell calcification"],"prefix":"10.1007","volume":"477","author":[{"given":"Mehdi","family":"Razazian","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheyda","family":"Bahiraii","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isratul","family":"Jannat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ad\u00e9la","family":"Tiffner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg","family":"Beilhack","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bodo","family":"Levkau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakob","family":"Voelkl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioana","family":"Alesutan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,2,3]]},"reference":[{"issue":"1","key":"3068_CR1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.advenzreg.2011.09.015","volume":"52","author":"A Aguilar","year":"2012","unstructured":"Aguilar A, Saba JD (2012) Truth and consequences of sphingosine-1-phosphate lyase. 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