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Selective Activation of PPAR and PPAR Induces Neoangiogenesis through a VEGF-dependent Mechanism

¹Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy
²Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA
³Department of Pathology, Catholic University School of Medicine, Rome, Italy
⁴Department of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, MA
⁵IRCCS OASI, Troina, Italy

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 mellitus (T2DM). 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 knock-out 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 eNOS and Akt.

Conclusions: These findings demonstrate that PPAR and PPAR activation stimulates neoangiogenesis through a VEGF-dependent mechanism. Neoangiogenesis is a crucial pathologic event in T2DM. The ability of PPAR and PPAR agonists to induce neoangiogenesis might have important implications for the clinical and therapeutic management of T2DM.

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