Abstract—Integrins play an important role in vascular smooth muscle cell (VSMC) migration, a crucial event in the development of restenosis and atherosclerosis. Transforming growth factor-&bgr; (TGF-&bgr;) is highly expressed in restenotic and atherosclerotic lesions, and known to induce integrin expression. Peroxisome proliferator-activated receptor &agr; (PPAR&agr;), a member of the nuclear receptor superfamily, regulates gene expression in a variety of vascular cells. We investigated the effects of PPAR&agr; ligands on TGF-&bgr;–induced &bgr;3and &bgr;5integrin expression and potential interaction between PPAR&agr; and TGF-&bgr; signaling. PPAR&agr; ligands WY-14643 (100 &mgr;mol/L) and 5,8,11,14-eicosatetranoic acid (ETYA, 50 &mgr;mol/L) inhibited TGF-&bgr;–induced &bgr;5integrin protein expression by 72±6.8% and 73±7.1%, respectively (bothP<0.05). TGF-&bgr;–stimulated &bgr;3integrin expression was not affected by PPAR&agr; ligands. Both PPAR&agr; ligands also suppressed TGF-&bgr;–induced &bgr;5integrin mRNA levels. PPAR&agr; ligands inhibited TGF-&bgr;–inducible transcription of &bgr;5integrin by an interaction with a TGF-&bgr; response element between nucleotides −63 and −44, which contains a Sp1/Sp3 transcription factor binding site. Nuclear complexes binding to the TGF-&bgr; response region contained Sp1/Sp3 and TGF-&bgr;–regulated Smad 2, 3, and 4 transcription factors. TGF-&bgr;–stimulated Sp1/Smad4 nuclear complex formation was inhibited by WY-14643 and ETYA with a parallel induction of PPAR&agr;/Smad4 interactions. However, in vitro pull-down experiments failed to demonstrate direct binding between PPAR&agr;/Smad4. Both PPAR&agr; ligands blocked PDGF-directed migration of TGF-&bgr;–pretreated VSMCs, a process mediated, in part, by &bgr;5integrins. The present study demonstrates that PPAR&agr; activators inhibit TGF-&bgr;–induced &bgr;5integrin transcription in VSMCs through a novel indirect interaction between ligand-activated PPAR&agr; and the TGF-&bgr;–regulated Smad4 transcription factors. The full text of this article is available at http://www.circresaha.org.