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The myogenic response in resistance arteries is responsible for basal (myogenic) tone and blood flow autoregulation. G\u2010protein\u2010coupled receptors and G\n                    <jats:sub>12<\/jats:sub>\n                    \/RhoA\/Rho kinase are implicated in myogenic tone (MT), and we aimed to clarify their role in pressure sensing and ageing. We studied MT in third\u2010order mesenteric arteries (MA)\n                    <jats:italic>ex vivo<\/jats:italic>\n                    and first\u2013fourth order cerebral arteries (CA) in vivo in young versus middle\u2010aged male mice. Inhibition of \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    \u2010, AT\n                    <jats:sub>1<\/jats:sub>\n                    \u2010, ET\n                    <jats:sub>A<\/jats:sub>\n                    \u2010 and TP\u2010receptors and thromboxane synthase did not affect MT in MA from young mice. The P2Y\u2010receptor blocker suramin inhibited MT, whereas PPADS and apyrase did not. MT in intact or endothelium\u2010denuded MAs was not affected by the knockout of P2Y\n                    <jats:sub>6<\/jats:sub>\n                    \u2010receptor (P2Y\n                    <jats:sub>6<\/jats:sub>\n                    \u2010R). qPCR showed upregulation of P2Y\n                    <jats:sub>2<\/jats:sub>\n                    \u2010R in P2Y\n                    <jats:sub>6<\/jats:sub>\n                    \u2010deficient arteries. MT was not affected in P2Y\n                    <jats:sub>2<\/jats:sub>\n                    \u2010R knock\u2010out mice. The sphingosine\u2010kinase (SK) blocker SKI\u2010II inhibited MT in young mice, and the sphingosine 1\u2010phosphate receptor 2 (S1P\n                    <jats:sub>2<\/jats:sub>\n                    \u2010R) blocker JTE\u2010013 inhibited MT in young and middle\u2010aged mice. MT was impaired in middle\u2010aged mice. Furthermore, MT was reduced in young mice carrying familial Alzheimer's disease mutations (5xFAD), and JTE\u2010013 abolished MT in 5xFAD mice and their wild\u2010type littermates. JTE\u2010013 did not affect calcium signalling in cultured human coronary artery smooth muscle cells. High\u2010resolution microangiography confirmed that infusion of JTE\u2010013 or KD025 (a Rho\u2010kinase 2 inhibitor) preferentially dilated small (distal) CAs, and infusion of nifedipine (an L\u2010type channel inhibitor) dilated all CAs in all mice, independent of age. SK and S1P\n                    <jats:sub>2<\/jats:sub>\n                    \u2010R are crucially involved in pressure sensing in MT. RhoA\/Rho\u2010kinase signalling might be involved in age\u2010related MT deficiency.\n                  <\/jats:p>","DOI":"10.1113\/ep093296","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T21:41:27Z","timestamp":1763415687000},"page":"1524-1542","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Role of S1P\u2010 and Rho\u2010kinase signalling in age\u2010related myogenic tone deficiency in murine resistance arteries"],"prefix":"10.1113","volume":"111","author":[{"given":"Gry Freja","family":"Skovsted","sequence":"first","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Science University of Copenhagen  Frederiksberg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Aupetit","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and 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