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 PPAR␣ and PPAR␥ stimulates neoangiogenesis.RESEARCH DESIGN AND METHODS-We used selective synthetic PPAR␣ and PPAR␥ agonists and investigated their angiogenic potentials in vitro and in vivo.RESULTS-Activation of PPAR␣ and PPAR␥ 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 PPAR␣ and PPAR␥ agonists are used in the murine corneal angiogenic model. No vascular growth is detectable when PPAR␣ and PPAR␥ agonists are respectively used in PPAR␣ knockout mice and mice treated with a specific PPAR␥ inhibitor, demonstrating that this angiogenic response is PPAR mediated. PPAR␣-and PPAR␥-induced angiogenesis is associated with local VEGF production and does not differ in extent and morphology from that induced by VEGF. In addition, PPAR␣-and PPAR␥-induced in vitro and in vivo angiogenesis may be significantly decreased by inhibiting VEGF activity. Finally, in corneas treated with PPAR␣ and PPAR␥ agonists, there is increased phosphorylation of endothelial nitric oxide synthase and Akt.CONCLUSIONS-These findings demonstrate that PPAR␣ and PPAR␥ activation stimulates neoangiogenesis through a VEGFdependent mechanism. Neoangiogenesis is a crucial pathological event in type 2 diabetes. The ability of PPAR␣ and PPAR␥ agonists to induce neoangiogenesis might have important implications for the clinical and therapeutic management of type 2 diabetes. Diabetes 57:1394-1404, 2008 P eroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors that belong to the nuclear hormone receptor superfamily (1). The clinical importance of PPARs originates with fibrates and thiazolidinediones (TZDs), which respectively act on PPAR␣ and PPAR␥ and are used to ameliorate hyperlipidemia and hyperglycemia in subjects with type 2 diabetes. Fibrates (gemfibrozil, clofibrate, fenofibrate, and bezofibrate) are drugs that effectively reduce triglycerides (TGs) and free fatty acids (FFAs) and increase HDL cholesterol (2-5). Fibrates also improve glucose tolerance in type 2 diabetic patients, although this activity might be attributable to the fact that some of these compounds also have potential PPAR␥ activity (6). TZDs (such as rosiglitazone, troglitazone, pioglitazone, and ciglitazone) are insulin-sensitizing drugs and have constituted a major advance in the recent therapeutic management of type 2 diabetes (7-9). In addition to improving insulin sensitivity, TZDs have also effects on TG, FFA, and ketone body level in several animal models of type 2 diabetes. Recently, PPAR␣/␥ dual agonists have also been produced, hypothesizing that the simultaneous activa...

Peroxisome proliferator-activated receptors as stimulants of angiogenesis in cardiovascular disease and diabetes

“…Biscetti et al used a selective synthetic PPAR-α agonist to demonstrate that activation of PPAR-α leads to endothelial tube formation in an endothelial/interstitial cell co-culture assay. 20 This study also showed that neovascularization occurs with PPARα activation in a murine corneal angiogenic model. In contrast no angiogenesis was found in PPAR-α knockout mice treated with this synthetic agonist.…”

“…In contrast no angiogenesis was found in PPAR-α knockout mice treated with this synthetic agonist. 20 In another study iloprost, an angiogenesis agent, was not able to induce angiogenesis in PPAR-α knockout mice. 21 In both these studies angiogenesis was stimulated through a PPAR-α induced VEGF upregulation.…”

MK886 inhibits the pioglitazone-induced anti-invasion of MDA-MB-231 cells is associated with PPARα/γ, FGF4 and 5LOX

“…Based on the findings of our study, the activation of PPARs, which increases the production of VEGF (Biscetti et al 2008), could not be fully linked to the expression of PPARa/c. However, our results indicate that this gene mRNA expression could be reversed by MK886 treatment.…”

Inflammation and Angiogenesis in Diabetic Retinopathy

“…Federico et al 39 tested selective PPAR and PPAR synthetic agonists potential ability to stimulate neoangiogenesis in well-established in vitro and in vivo assays. They found that specific and selective activation of PPAR and PPAR leads to increased production of VEGF, a prototypical angiogenic agent, and formation of endothelial tubules when endothelial cells are co-cultured with interstitial cells.…”