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Published online February 11, 2008
Diabetes 57:1394-1404, 2008
DOI: 10.2337/db07-0765
© 2008 by the American Diabetes Association
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Selective Activation of Peroxisome Proliferator–Activated Receptor (PPAR){alpha} and PPAR{gamma} Induces Neoangiogenesis Through a Vascular Endothelial Growth Factor–Dependent Mechanism

Federico Biscetti1, Eleonora Gaetani1, Andrea Flex1, Tamar Aprahamian2, Teresa Hopkins2, Giuseppe Straface1, Giovanni Pecorini1, Egidio Stigliano3, Roy C. Smith4, Flavia Angelini1, John J. Castellot, Jr.4, and Roberto Pola1,4,5

1 Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy
2 Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
3 Department of Pathology, Catholic University School of Medicine, Rome, Italy
4 Department of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, Massachusetts
5 Istituto di Ricovero e Cura a Carattere Scientifico Oasi, Troina, Italy

Corresponding author: Roberto Pola, MD, PhD, Department of Anatomy and Cell Biology, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. E-mail: roberto.pola{at}tufts.edu

Abbreviations: eNOS, endothelial nitric oxide synthase; FBS, fetal bovine serum; FFA, free fatty acid; HDMVEC, human dermal microvascular endothelial cell; HUVEC, human umbilical vein endothelial cell; PPAR, peroxisome proliferator–activated receptor; TG, triglyceride; TZD, thiazolidinedione; VEGF, vascular endothelial growth factor

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{alpha} 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 PPAR{alpha} and PPAR{gamma} 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{alpha} and PPAR{gamma} agonists are used in the murine corneal angiogenic model. No vascular growth is detectable when PPAR{alpha} 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, PPAR{alpha}- and PPAR{gamma}-induced in vitro and in vivo angiogenesis may be significantly decreased by inhibiting VEGF activity. Finally, in corneas treated with PPAR{alpha} and PPAR{gamma} agonists, there is increased phosphorylation of endothelial nitric oxide synthase and Akt.

CONCLUSIONS—These findings demonstrate that PPAR{alpha} 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{alpha} and PPAR{gamma} agonists to induce neoangiogenesis might have important implications for the clinical and therapeutic management of type 2 diabetes.


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