Protease-activated receptor-2 stimulates angiogenesis and accelerates hemodynamic recovery in a mouse model of hindlimb ischemia

Anna F Milia, Maria B Salis, Tiziana Stacca, Alessandra Pinna, Paolo Madeddu, Marcello Trevisani, Pierangelo Geppetti, Costanza Emanueli

Research output: Contribution to journalArticle (Academic Journal)peer-review

72 Citations (Scopus)


Proteinase-activated receptors (PAR-2) are expressed by the cardiovascular system and mediate vasodilation, plasma protein extravasation, and endothelial cell proliferation, all regarded as essential steps for neovascularization. We investigated the angiogenic action of PAR-2 signaling in vivo. The effect of the PAR-2 activating peptide (PAR-2AP, SLIGRL-NH2) was assessed in the absence of ischemia, and the therapeutic potential of PAR-2AP and the PAR-2 agonist trypsin (at 300 and 1.5 nmol IM daily for 21 days, respectively) was also tested in mice subjected to unilateral limb ischemia. PAR-2AP increased capillarity in normoperfused adductor skeletal muscles, whereas neither the vehicle of the PAR2-AP nor the PAR-2 reverse peptide (PAR-2RP, LRGILS-NH2) did produce any effect. In addition, both PAR-2AP and trypsin enhanced reparative angiogenic response to limb ischemia, an effect that was not produced by PAR-2RP or the vehicle of PAR-2 agonists. Potentiation of reparative angiogenesis by PAR-2AP or trypsin resulted in an accelerated hemodynamic recovery and enhanced limb salvage. In conclusions, our study is the first to demonstrate the angiogenic potential of PAR-2 stimulation in vivo. If similar effects occur in humans, PAR-2AP agonists could have some therapeutic potential for the treatment of tissue ischemia.

Translated title of the contributionProtease-Activated Receptor-2 Stimulates Angiogenesis and Accelerates Hemodynamic Recovery in a Mouse Model of Hindlimb Ischemia
Original languageEnglish
Pages (from-to)346 - 352
Number of pages7
JournalCirculation Research
Issue number4
Publication statusPublished - 23 Aug 2002

Bibliographical note

Publisher: Lippincott, Williams & Wilkins


  • Animals
  • Capillaries
  • Disease Models, Animal
  • Gene Expression Regulation
  • Hemodynamics
  • Hindlimb
  • Injections, Intramuscular
  • Ischemia
  • Laser-Doppler Flowmetry
  • Male
  • Mice
  • Muscle, Skeletal
  • Neovascularization, Physiologic
  • Oligopeptides
  • Receptor, PAR-2
  • Receptors, Thrombin
  • Recovery of Function
  • Regional Blood Flow
  • Up-Regulation


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