Selective activation of peroxisome proliferator-activated receptor (PPAR)α and PPARγ induces neoangiogenesis through a vascular endothelial growth factor-dependent mechanism

OBJECTIVE-Peroxisome proliferator-activated receptors (PPARs) are therapeutic targets for fibrates and thiazolidinedio-nes, which are commonly used to ameliorate hyperlipidemia and hyperglycemia in type 2 diabetes. In this study, we evaluated whether activation of PPARα and PPAR7 stimulates neoangio-genesis. RESEARCH DESIGN AND METHODS-We used selective synthetic PPARa and PPAR7 agonists and investigated their angiogenic potentials in vitro and in vivo. RESULTS-Activation of PPARα and PPAR7 leads to endothe-lial tube formation in an endothelial/interstitial cell co-culture assay. This effect is associated with increased production of the angiogenic cytokine vascular endothelial growth factor (VEGF). Neovascularization also occurs in vivo, when PPARα and PPARγagonists are used in the murine corneal angiogenic model. No vascular growth is detectable when PPARα and PPAR7 agonists are respectively used in PPARa knockout mice and mice treated with a specific PPARγ inhibitor, demonstrating that this angiogenic response is PPAR mediated. PPARγ-and PPARγ-induced angiogenesis is associated with local VEGF production and does not differ in extent and morphology from that induced by VEGF. In addition, PPARα-and PPARγ-induced in vitro and in vivo angiogenesis may be significantly decreased by inhibiting VEGF activity. Finally, in corneas treated with PPARα and PPARγ agonists, there is increased phosphorylation of endothelial nitric oxide synthase and Akt. CONCLUSIONS-These findings demonstrate that PPARα and PPARγ activation stimulates neoangiogenesis through a VEGF-dependent mechanism. Neoangiogenesis is a crucial pathological