Deletion of RSK2 kinase alleviates age-dependent hypertension

Somlyo, A. V.; Ayon, R. J.; Wang, Y. T.; Kalra, J. K.; Jin, L.; Chen, Y. L.; Polanowska-Grabowska, R.; Sonkusare, S. K.; Christie, C. K.; Small, E. M.; Le, T. H.

doi:10.1101/2025.03.12.642932

bioRxiv · 10.1101/2025.03.12.642932

Deletion of RSK2 kinase alleviates age-dependent hypertension

Somlyo, A. V.·Ayon, R. J.·Wang, Y. T.·Kalra, J. K.·Jin, L.·Chen, Y. L.·Polanowska-Grabowska, R.·Sonkusare, S. K.·Christie, C. K.·Small, E. M.·Le, T. H.

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Abstract

BackgroundHypertension 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). MethodsBasal 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. ResultsResting 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 Hb distribution at myoendothelial junctions were disturbed impairing vasorelaxation in aged Rsk2+/+ but not aged Rsk2-/- arterioles. ConclusionsRSK2 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.

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Somlyo, A. V., Ayon, R. J., Wang, Y. T., Kalra, J. K., Jin, L., Chen, Y. L., Polanowska-Grabowska, R., Sonkusare, S. K., Christie, C. K., Small, E. M., Le, T. H.. 2025-03-14. Deletion of RSK2 kinase alleviates age-dependent hypertension. https://doi.org/10.1101/2025.03.12.642932

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