Selective Activation of Peroxisome Proliferator–Activated Receptor (PPAR)α and PPARγ Induces Neoangiogenesis Through a Vascular Endothelial Growth Factor–Dependent Mechanism

Abstract

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 PPARα and PPARγ stimulates neoangiogenesis. RESEARCH DESIGN AND METHODS—We used selective synthetic PPARα and PPARγ agonists and investigated their angiogenic potentials in vitro and in vivo. RESULTS—Activation of PPARα and PPARγ leads to endothelial 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 PPARγ agonists are used in the murine corneal angiogenic model. No vascular growth is detectable when PPARα and PPARγ agonists are respectively used in PPARα knockout mice and mice treated with a specific PPARγ inhibitor, demonstrating that this angiogenic response is PPAR mediated. PPARα- 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 event in type 2 diabetes. The ability of PPARα and PPARγ agonists to induce neoangiogenesis might have important implications for the clinical and therapeutic management of type 2 diabetes.