Research Paper

Peroxisome Proliferator-Activated Receptor Alpha Is Crucial for Iloprost-Induced in vivo Angiogenesis and Vascular Endothelial Growth Factor Upregulation
Federico Biscetti^a, Eleonora Gaetani^a, Andrea Flex^a, Giuseppe Straface^a, Giovanni Pecorini^a, Flavia Angelini^a, Egidio Stigliano^b, Tamar Aprahamian^d, Roy C. Smith^e, John J. Castellot^e, Roberto Pola<sup>a, c, e

a</sup>Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital and
^bDepartment of Pathology, Catholic University School of Medicine, Rome, and
^cIRCCS OASI, Troina, Italy;
^dMolecular Cardiology, Boston University School of Medicine, and
^eDepartment of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, Mass., USA

Address of Corresponding Author

J Vasc Res 2009;46:103-108 (DOI: 10.1159/000143793)

  Key Words

• Iloprost
• Prostacyclin
• Peroxisome proliferator-activated receptor-
• Angiogenesis
• Vascular endothelial growth factor

  Abstract

We have previously demonstrated that iloprost, a stable prostacyclin (PGI₂) analogue, induces angiogenesis in vivo, through a vascular endothelial growth factor (VEGF)-dependent mechanism. In this study, we demonstrate that iloprost-induced angiogenesis and VEGF upregulation are modulated by peroxisome proliferator-activated receptor- (PPAR), a ligand-inducible transcription factor that belongs to the nuclear hormone receptor superfamily and plays multiple biological activities in the vascular system. We show that iloprost is unable to induce angiogenesis in mice lacking the PPAR gene (PPAR-/- mice). Likewise, iloprost-induced VEGF upregulation is absent in PPAR-/- mice. In contrast, iloprost induces a robust angiogenic response in wild-type mice, along with local upregulation of VEGF. Importantly, mice lacking the PPAR gene exhibit a normal angiogenic response to VEGF, indicating that the absence of PPAR does not result in a general impairment of angiogenesis, but specifically affects the ability of iloprost to induce angiogenesis. Our data demonstrate unexpected functional relationships between the PGI₂ system and the PPAR signaling pathway and shed new light on the molecular mechanisms involved in iloprost-induced angiogenesis.

Copyright © 2008 S. Karger AG, Basel

  Author Contacts

Dr. Roberto Pola
Department of Anatomy and Cell Biology
Tufts University School of Medicine
136 Harrison Avenue, Boston, MA 02111 (USA)
Tel. +1 617 636 0303, Fax +1 617 636 6536, E-Mail roberto.pola@tufts.edu

  Article Information

Received: January 18, 2008
Accepted after revision: April 10, 2008
Published online: July 10, 2008
Number of Print Pages : 6
Number of Figures : 4, Number of Tables : 0, Number of References : 17