Vascular Smooth Muscle Cell Peroxisome Proliferator-Activated Receptor-γ Mediates Pioglitazone-Reduced Vascular Lesion Formation

Objective-Peroxisome proliferator-activated receptor-gamma (PPAR gamma) has been reported to decrease vascular lesion formation. However, the critical role of vascular smooth muscle cell (VSMC) PPAR gamma in vascular lesion formation following transplantation is not well understood. In this study, we investigated the role of VSMC PPAR gamma-mediated signaling in transplantation-associated vascular lesion formation. Methods and Results-Carotid arteries from smooth muscle cell-selective PPAR gamma knockout (SMPG KO) and wild-type mice were transplanted to CBA/CaJ recipient mice. The recipient mice received a control diet or pioglitazone-containing diet. Pioglitazone reduced vascular lesion formation in transplanted wild-type, but not in SMPG KO carotid arteries. Histological analysis suggested that PPAR gamma attenuates vascular lesion formation through antiinflammatory signaling, as evidenced by the increase of intimal inflammatory cells and tumor necrosis factor-alpha expression in SMPG KO allografts. Intravital microscopy revealed increased inflammatory cell rolling and attachment to endothelial cells in small blood vessels of SMPG KO mice following cytokine stimulation. SMPG KO mice, as shown by Western blotting, have elevated vascular cell adhesion molecule-1 (VCAM-1) expression. Furthermore, immunohistochemistry demonstrated SMPG KO allografts have increased VCAM-1. Conclusion-Loss of PPAR gamma in VSMC promotes transplantation-associated vascular lesion formation through increased VCAM-1 expression. VSMC PPAR gamma also mediates pioglitazone-reduced vascular lesion formation. (Arterioscler Thromb Vasc Biol. 2011;31:352-359.)