Abstract Body: Background: Hypertension prevalence increases with age, reaching over 70% of people over age 65. The underlying mechanisms are poorly understood. This study interrogates a new signaling pathway in vascular smooth muscle of aged mice driven by p90 ribosomal S6 kinase, RSK2, and its role in increasing peripheral vascular resistance and blood pressure (BP).
Methods: Basal BP measurements were taken at 26-29 month (812-892 day) old mice with global deletion of RSK2 (Rsk2^-/-) prior to and following treatment with L-NAME. Cardiac function, vessel stiffness, myogenic responses, Ca²⁺events, contractility, immuno-staining, histology studies and western blotting were performed.
Results: Resting BP and myogenic vasoconstriction were normal in aged global Rsk2^-/- mice and elevated in wild type (WT) littermates. L-NAME treatment increased BP in aged Rsk2^+/+ but not aged Rsk2^-/-. Vessel stiffness and glycation collagen crosslinking increased in both aged Rsk2^+/+ and Rsk2^-/- compared to young vessels with no remodeling or increase in collagen content, even though BP in aged Rsk2^-/- arterioles was normal. Increased vessel stiffness was dissociated from increased BP. Ca²⁺ transients increased and sensitivity to NO-induced relaxation decreased in aged Rsk2^+/+ compared to young WT arterioles. IEL structures, eNOS and Hbα distribution at myoendothelial junctions were disturbed impairing vasorelaxation in aged Rsk2^+/+ but not aged Rsk2^-/- arterioles.
Conclusions: RSK2 plays a significant role in hypertension associated with aging by downregulating prorelaxant signaling and promoting procontractile events in the vasculature, offering potential new therapeutic targets.