RSK2 contributes to myogenic vasoconstriction of resistance arteries by activating smooth muscle myosin and the Na/H exchanger.

Smooth muscle contraction is triggered when Ca/calmodulin-dependent myosin light chain kinase (MLCK) phosphorylates the regulatory light chain of myosin (RLC). However, blood vessels from -deficient mouse embryos retain the ability to contract, suggesting the existence of additional regulatory mechanisms. We showed that the p90 ribosomal S6 kinase 2 (RSK2) also phosphorylated RLC to promote smooth muscle contractility. Active, phosphorylated RSK2 was present in mouse resistance arteries under normal basal tone, and phosphorylation of RSK2 increased with myogenic vasoconstriction or agonist stimulation. Resistance arteries from -deficient mice were dilated and showed reduced myogenic tone and RLC phosphorylation. RSK2 phosphorylated Ser in RLC in vitro. In addition, RSK2 phosphorylated an activating site in the Na/H exchanger (NHE-1), resulting in cytosolic alkalinization and an increase in intracellular Ca that promotes vasoconstriction. NHE-1 activity increased upon myogenic constriction, and the increase in intracellular pH was suppressed in -deficient mice. In pressured arteries, RSK2-dependent activation of NHE-1 was associated with increased intracellular Ca transients, which would be expected to increase MLCK activity, thereby contributing to basal tone and myogenic responses. Accordingly, -deficient mice had lower blood pressure than normal littermates. Thus, RSK2 mediates a procontractile signaling pathway that contributes to the regulation of basal vascular tone, myogenic vasoconstriction, and blood pressure and may be a potential therapeutic target in smooth muscle contractility disorders.