Abstract —Migration of vascular smooth muscle cells (VSMCs) plays an important role in atherogenesis and restenosis after arterial interventions. The expression of matrix metalloproteinases (MMPs), particularly MMP-9, contributes to VSMC migration. This process requires degradation of basal laminae and other components of the arterial extracellular matrix. Peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor family, regulate gene expression after activation by various ligands. Recent studies have suggested opposing effects of PPAR gamma (PPARγ) activation on atherogenesis. The present study tested the hypotheses that human VSMCs express PPAR alpha (PPARα) and PPARγ and that PPAR agonists in VSMCs modulate MMP-9 expression and activity, as well as VSMC migration. Human VSMCs expressed PPARα and PPARγ mRNA and protein. Treatment of VSMCs with the PPARγ ligands troglitazone and the naturally occurring 15-deoxy- Δ12,14 -prostaglandin J 2 (15d-PGJ 2 ) decreased phorbol 12-myristate 13-acetate–induced MMP-9 mRNA and protein levels, as well as MMP-9 gelatinolytic activity in the supernatants in a concentration-dependent manner. Six different PPARα activators lacked such effects. Addition of prostaglandin F 2α , known to limit PPARγ activity, diminished the MMP-9 inhibition seen with either troglitazone or 15d-PGJ 2 , further implicating PPARγ in these effects. Finally, troglitazone and 15d-PGJ 2 inhibited the platelet-derived growth factor-BB–induced migration of VSMCs in vitro in a concentration-dependent manner. PPARγ activation may regulate VSMC migration and expression and activity of MMP-9. Thus, PPARγ activation in VSMCs, via the antidiabetic agent troglitazone or naturally occurring ligands, may act to counterbalance other potentially proatherosclerotic PPARγ effects.