PPAR-γ promotes endothelial cell migration by inducing the expression of Sema3g.

In addition to regulating lipid and glucose metabolism, the nuclear receptor PPAR-γ has emerged as a potentially relevant player in regulating endothelial cell function. Despite the identification of numerous PPAR-γ targets involved in vascular development, the targets downstream of PPAR-γ that directly affect endothelial cell function remain to be elucidated. In this report, we identify Sema3g as a novel PPAR-γ-regulated gene playing a substantial role in endothelial biology, particularly with respect to endothelial cell migration. Sema3g expression is induced by either overexpression of PPAR-γ or PPAR-γ ligands treatment in human umbilical vein endothelial cells (HUVECs). Chromatin immunoprecipitation (ChIP) and transient transfection assays revealed that PPAR-γ binds to the Sema3g promoter and activates transcription. Furthermore, we show that overexpression of Sema3g augments PPAR-γ-driven HUVECs migration, whereas silencing of Sema3g expression almost completely abrogates PPAR-γ or Sema3g-mediated cell migration. Accordingly, the anti-neuropilin-2 (Sema3g receptor) neutralizing antibody treatment markedly inhibits Sema3g-induced cell migration. Collectively, these results identify Sema3g as one of the downstream effectors of PPAR-γ, which is centrally involved in regulating endothelial cell migration.