Role of S1P‐ and Rho‐kinase signalling in age‐related myogenic tone deficiency in murine resistance arteries

Ageing is a risk factor for cardiovascular and neurodegenerative diseases. The myogenic response in resistance arteries is responsible for basal (myogenic) tone and blood flow autoregulation. G‐protein‐coupled receptors and G 12 /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‐order mesenteric arteries (MA) ex vivo and first–fourth order cerebral arteries (CA) in vivo in young versus middle‐aged male mice. Inhibition of α 1 ‐, AT 1 ‐, ET A ‐ and TP‐receptors and thromboxane synthase did not affect MT in MA from young mice. The P2Y‐receptor blocker suramin inhibited MT, whereas PPADS and apyrase did not. MT in intact or endothelium‐denuded MAs was not affected by the knockout of P2Y 6 ‐receptor (P2Y 6 ‐R). qPCR showed upregulation of P2Y 2 ‐R in P2Y 6 ‐deficient arteries. MT was not affected in P2Y 2 ‐R knock‐out mice. The sphingosine‐kinase (SK) blocker SKI‐II inhibited MT in young mice, and the sphingosine 1‐phosphate receptor 2 (S1P 2 ‐R) blocker JTE‐013 inhibited MT in young and middle‐aged mice. MT was impaired in middle‐aged mice. Furthermore, MT was reduced in young mice carrying familial Alzheimer's disease mutations (5xFAD), and JTE‐013 abolished MT in 5xFAD mice and their wild‐type littermates. JTE‐013 did not affect calcium signalling in cultured human coronary artery smooth muscle cells. High‐resolution microangiography confirmed that infusion of JTE‐013 or KD025 (a Rho‐kinase 2 inhibitor) preferentially dilated small (distal) CAs, and infusion of nifedipine (an L‐type channel inhibitor) dilated all CAs in all mice, independent of age. SK and S1P 2 ‐R are crucially involved in pressure sensing in MT. RhoA/Rho‐kinase signalling might be involved in age‐related MT deficiency.