Aging is a risk factor for cardiovascular and neurodegenerative diseases. The myogenic response in resistance arteries is crucial for basal tone and blood flow autoregulation. G-protein-coupled receptors and G12/RhoA/Rho-kinase were suggested to play a role in myogenic tone (MT), but the pressure sensor and role of aging is incompletely understood. We used pressure myography, calcium imaging, qPCR for studying 3rd order mesenteric arteries (MA), and in vivo synchrotron radiation microangiography (SPring-8, Japan) for 0-4th order
cerebral arteries (CA) in young (2-5 month; N=8) vs. middle-aged (11-14 month; N=8) mice. Inhibition of α1-, AT1-, ETA-, TP-receptors and thromboxane synthase did not affect MT in MA from young mice. P2Y-receptor
blocker suramin (100 μM) inhibited MT, whereas PPADS (10 μM) and apyrase (20 U/mL) did not. MT in intact or endothelium-denuded arteries were not different between P2Y6-R KO and WT mice. qPCR detected upregulation of P2Y2-R in MA from P2Y6-R KO mice. However, MT was not different between P2Y2-R KO and WT mice. The sphingosine-kinase (SK) blocker SKI-II (75 μM) inhibited MT in young mice, and the S1PR blocker JTE-013 (1.6 and 5 μM) potently inhibited MT in both age groups. JTE-013 (5 μM) did not affect calcium signaling in VSMCs. Overall, MT was strongly suppressed in middle-aged mice. Preliminary analyses showed that inhibitors of S1PR (JTE-013), Rho-kinase (KD025), and L-type channels (nifedipine) dilated CA in all mice. SK and S1PR2-receptors play an age-independent role in pressure sensing in MT. We speculate that Rho-kinase is involved in age-dependent suppression of MT.