Abstract 15590: Smooth Muscle Specific Deletion of P90 Ribosomal S6 Kinase Alters the Vasomotor Response of Resistance Arteries

Background: Smooth muscle (SM) contraction is triggered by Ca 2+ /calmodulin-dependent myosin light chain kinase (MLCK), which phosphorylates the regulatory light chain of myosin (RLC 20 ). However, additional regulatory mechanisms exist. We found that global Rsk2 KO mice had more dilated mesenteric arteries (MAs) with reduced myogenic tone and RLC 20 phosphorylation, and significantly lower blood pressure. Furthermore, RSK2-dependent activation of the Na + /H + exchanger resulted in an increase in pH i and increased Ca 2+ i transients. However, it is unclear whether our observations were due to developmental abnormalities observed in Rsk2 global KO mice. Hypothesis: RSK2 signaling in SM is a significant regulator of myogenic tone, arterial stiffness, and Ca 2+ signaling. Methods: To study the role of RSK2 signaling in vascular tone, we generated inducible SM-specific RSK2 KO mice. Detection of total and phospho proteins were determined by western blot. Pressure myography studies assessed vascular reactivity in 4 th - and 5 th -order MAs isolated from MYH11-Cre + Rsk2 fl/fl (RSK2 SM -/- ) and MYH11-Cre - Rsk2 fl/fl (RSK2 SM +/+ ) mice. We examined SM-specific Ca 2+ events in pressurized MAs by confocal fluorescent microscopy. Results: Western blot confirms knock down of RSK2 expression (~70%) in MAs and aorta. Intraluminal pressure-induced constriction of MAs is attenuated in RSK2 SM -/- . RSK2 SM -/- MAs display a delay in development of myogenic tone at 40 mmHg and decreased vascular stiffness, compared to RSK2 SM +/+ . Vasodilatory responses to Spermine NONOate (1-100 μM) in preconstricted (L-NNA; 10 μM) RSK2 SM -/- vessels were enhanced. RSK2 SM -/- MAs display fewer Ca 2+ events (97±19.6; n = 4) than RSK2 SM +/+ (400±24.5; n = 4) at 80 mmHg ( p = 0.0001). Additionally, Ca 2+ events are slower and longer-lasting in the RSK2 SM -/- . Decreased levels of p-RLC 20 are observed at 40 mmHg, but not 80 mmHg in RSK2 SM -/- vs. RSK2 SM +/+ mice, consistent with impeding tone development. Conclusion: RSK2 signaling contributes to myogenic tone and vessel stiffness by regulating sensitivity to NO, increasing Ca 2+ events, and RLC 20 activity. RSK2 signaling pathway is a potential therapeutic target for hypertension.