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 thiazolidinediones, which are commonly used to ameliorate hyperlipidemia and hyperglycemia in type 2 diabetes. In this study, we evaluated whether activation of PPAR(x and PPAR-gamma stimulates neoangiogenesis. RESEARCH DESIGN AND METHODS-We used selective synthetic PPAR alpha and PPAR gamma agonists and investigated their angiogenic potentials in vitro and in vivo. RESULTS-Activation of PPARa and PPAR gamma leads to endothelia 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 PPAR alpha and PPAR gamma agonists are used in the murine corneal angiogenic model. No vascular growth is detectable when PPARa and PPAR gamma agonists are respectively used in PPAR alpha knockout mice and mice treated with a specific PPAR gamma inhibitor, demonstrating that this angiogenic response is PPAR mediated. PPAR alpha- and PPAR gamma-induced angiogenesis is associated with local VEGF production and does not differ in extent and morphology from that induced by VEGF. In addition, PPARa- and PPAR gamma-induced in vitro and in vivo angiogenesis may be significantly decreased by inhibiting VEGF activity. Finally, in corneas treated with PPARa and PPAR gamma agordsts, there is increased phosphorylation of endothelial nitric oxide synthase and Akt. CONCLUSIONS-These findings demonstrate that PPARa and PPAR gamma activation stimulates neoangiogenesis through a VEGF-dependent mechanism. Neoangiogenesis is a crucial pathological event in type 2 diabetes. The ability of PPAR(x and PPAR gamma agonists to induce neoangiogenesis might have important imphcations for the clinical and therapeutic management of type 2 diabetes.