Abstract Body: Vascular smooth muscle cells (VSMCs) participate in atherogenesis, during which VSMCs undergo phenotypic modulation from a contractile phenotype to a fibroproliferative phenotype. Within plaques, SMCs deposit extracellular matrix to form a fibrous cap that stabilizes the plaque. EphA2, a cancer-associated receptor tyrosine kinase, was recently shown to play a role in atherogenesis. We determined that EphA2 regulates SMC phenotype and proliferation both in vitro and in vivo. Interestingly, our data show that EphA2 is required for maximal SMC proliferation and migration, but is detrimental to both processes, dependent upon the context of EphA2 activation in that EphA2 ligation antagonizes Erk1/2 and Akt activation, proliferation, and migration. Further, serum treatment of VSMCs promotes robust S897 (ligand-independent) activation and promotes proliferation and migration. The S897 activating kinase differs between stimuli; but, in VSMCs, we observe that only Erk1/2 and RSK inhibition blunts S897 phosphorylation. RSK activation is Erk-dependent, so we used siRNA against RSK1 and RSK2 and observed that loss of RSK2 significantly reduces S897 activation. Interestingly, RSK2-KD abrogation of S897 phosphorylation did not affect SMC proliferation, but does prevent EphA2 localization to lamellipodia structures, implicating S897 phosphorylation in VSMC migration. Lastly, a 14 day wire injury model in SMC-EphA2 KO mice revealed significantly reduced medial expansion and SMC proliferation. Understanding how EphA2 modulates SMC behavior in terms of phenotypic modulation, migration, and proliferation will provide a basis to target this receptor to stabilize plaques, preventing deadly thrombotic events.