Since chronic inflammation is associated with the pathogenesis of atherosclerosis, inflammatory cytokines might contribute to the phenotypic modulation of vascular smooth muscle cells (VSMCs). Tumor necrosis factor α (TNFα) facilitated the transformation of contractile VSMCs to the synthetic phenotype, as determined by the expression of marker proteins and a collagen gel contraction assay. Western blot analysis and a cyclooxygenase-2 (COX2) promoter assay revealed that TNFα stimulation resulted in the induction of COX2. The overexpression, silencing, or pharmacological inhibition of COX2 significantly affected TNFα-induced phenotypic conversion, and of the tested prostaglandins, only PGD 2 significantly induced phenotypic conversion. ERK was significantly activated by PGD 2 stimulation, and the pharmacological inhibition of ERK blocked the PGD 2-induced phenotypic conversion of VSMCs. However, antagonists or agonists of PGD 2 receptors did not affect VSMC conversion. In contrast, spontaneously dehydrated forms of PGD 2 , such as PGJ 2 , Δ 12-PGJ 2 , and 15-d-PGJ 2 , strongly induced phenotypic conversion. A reporter gene assay showed that TNFα, PGD 2 , and 15-d-PGJ 2 significantly activated the peroxisome proliferator-responsive element (PPRE) promoter. In addition, the overexpression or silencing of peroxisome proliferator-activated receptor δ (PPARδ) significantly influenced 15-d-PGJ 2-induced phenotypic conversion. Finally, atherosclerotic neointima formation was significantly suppressed in mice lacking TNFα. In addition, mice fed celecoxib exhibited complete inhibition of carotid artery ligation-induced neointima formation. This study shows that PGD 2 regulates the phenotypic conversion of VSMCs by generating an endogenous ligand of PPAR, and that this leads to neointima formation in occlusive arterial disease.