Abstract 14369: Smooth Muscle Specific Deletion of RSK2 Suppresses Vasoconstriction of Resistance Arteries

Abstract

Introduction: Intracellular Ca 2+ is a vital second messenger that plays a fundamental role in regulating intraluminal pressure- and agonist-induced vasoconstriction. Our laboratory previously demonstrated that intraluminal pressure and G-protein coupled receptor agonist stimulation activate p90 ribosomal S6 kinase 2 (RSK2). RSK2, in turn, phosphorylates the regulatory light chain of myosin (RLC 20 ) to induce constriction of small, resistance-sized arteries. More recently, we discovered that resistance arteries from global KO RSK2 mice exhibited a more dilated luminal diameter, reduced myogenic tone and RLC 20 phosphorylation, and decreased blood pressure. However, it is unclear whether the observed effects are a result of RSK2 global deletion in the mouse which may cause developmental abnormalities affecting the cardiovascular system. Hypothesis: We hypothesize that smooth muscle-specific RSK2 signaling in mouse resistance arteries is a significant regulator of myogenic tone and arterial stiffness. Methods: Inducible smooth muscle-specific KO mice for RSK2 (RSK2 SMC-/- ) were generated to study the role of RSK2 signaling in the regulation of vascular tone. Pressure myography studies assessed vascular reactivity in 4 th - and 5 th -order mesenteric arteries (MAs) isolated from RSK2 SMC-/- and RSK2 fl/fl mice. Results: The downregulation of normal RSK2 expression in resistance arteries was confirmed by Western blot. Our data shows that the intraluminal pressure-induced constriction of MAs is significantly attenuated in RSK2 SMC-/- mice (n=7 each group). Additionally, RSK2 SMC-/- resistance arteries experienced a delay in development of myogenic tone at 40 mmHg indicating that RSK2 signaling is sensitive to small changes in intraluminal pressure. Furthermore, MAs from RSK2 SMC-/- mice exhibited decreased vascular stiffness (indicated by enhanced strain, and rightward shift of stress-strain relationship) when compared to MAs from RSK2 fl/fl mice. Conclusions: This study provides novel evidence that smooth muscle RSK2 signaling contributes to pressure-induced vasoconstriction, and vascular stiffness. Inhibiting smooth muscle RSK2 activity may represent a novel strategy for rescuing vascular function in hypertensive patients.