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Deletion of RSK2 kinase alleviates age-dependent hypertension
Ramon Ayon1, Yves T Wang1,2, Jaspreet Kalra1
1Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
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.
Insights
Aging hypertension involves RSK2 signaling in vascular smooth muscle. Deleting RSK2 in aged mice normalized blood pressure, revealing RSK2 as a therapeutic target for age-related hypertension.
Area of Science:
- Cardiovascular Biology
- Vascular Physiology
- Aging Research
Background:
- Hypertension prevalence significantly increases with age, affecting over 70% of individuals over 65.
- The precise mechanisms driving age-related hypertension remain incompletely understood.
- This study investigates the role of p90 ribosomal S6 kinase, RSK2, in vascular smooth muscle during aging.
Purpose of the Study:
- To elucidate the function of RSK2 in the development of hypertension in aged mice.
- To determine the impact of RSK2 deletion on peripheral vascular resistance and blood pressure in aging.
- To identify potential therapeutic targets for age-associated increases in blood pressure.
Main Methods:
- Assessed basal blood pressure (BP) in aged mice with and without RSK2 deletion, with and without L-NAME treatment.
- Performed cardiac function tests, vessel stiffness analysis, myogenic responses, calcium (Ca2+) imaging, contractility assays, and molecular analyses (immunostaining, histology, Western blotting).
Main Results:
- Aged mice lacking RSK2 (Rsk2-/-) exhibited normal resting BP and myogenic vasoconstriction, unlike wild-type (WT) littermates.
- L-NAME administration elevated BP in aged WT mice but not in aged Rsk2-/- mice.
- While aged Rsk2-/- mice had normal BP, they showed increased vessel stiffness and collagen crosslinking, suggesting dissociation between stiffness and elevated BP. Vasorelaxation was impaired due to disturbed IEL structures and altered eNOS/Hbα distribution.
Conclusions:
- RSK2 plays a critical role in mediating hypertension associated with aging.
- RSK2 downregulates pro-relaxant signaling and promotes pro-contractile events in the aged vasculature.
- Targeting RSK2 presents a potential therapeutic strategy for managing age-related hypertension.
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