The development of numerous types of cardiovascular disease is associated with alteration of the vascular smooth muscle cell (SMC) phenotype. We have previously shown that abdominal aortic aneurysm progression in a mouse model of the disease is associated with reduced differentiation of SMCs within the lesion and that cyclooxygenase-2 (COX-2) is critical to initiation and progression of the aneurysms. The current studies utilized human aortic SMC (hASMC) cultures to better characterize mechanisms responsible for COX-2-dependent modulation of the SMC phenotype. Depending on the culture conditions, hASMCs expressed multiple characteristics of a differentiated and contractile phenotype, or a de-differentiated and secretory phenotype. The pharmacological inhibition of COX-2 promoted the differentiated phenotype whereas treatment with the COX-2-derived metabolite prostaglandin E2 (PGE2) increased characteristics of the de-differentiated phenotype. Furthermore, pharmacological inhibition or siRNA-mediated knockdown of microsomal prostaglandin E synthase-1 (mPGES-1), the enzyme that functions down-stream of COX-2 during the synthesis of PGE2, significantly increased expression of characteristics of the differentiated SMC phenotype. Therefore, our findings suggest that COX-2 and mPGES-1 -dependent synthesis of PGE2 contributes to a de-differentiated hASMC phenotype and that mPGES-1 may provide a novel pharmacological target for treatment of cardiovascular diseases where altered SMC differentiation has a causative role.