Published online before print August 1, 2002, doi: 10.1161/01.RES.0000031958.92781.9E
© 2002 American Heart Association, Inc.
Integrative Physiology |
Protease-Activated Receptor-2 Stimulates Angiogenesis and Accelerates Hemodynamic Recovery in a Mouse Model of Hindlimb Ischemia
From the Cardiovascular Medicine and Gene Therapy Section (A.F.M., M.B.S., T.S., A.P., P.M., C.E.), National Laboratory of the National Institute of Biostructures and Biosystems (INBB), Osilo (Sassari), Italy; Internal Medicine (P.M.), University of Sassari, Italy; and Experimental and Clinical Medicine (M.T., P.G.), University of Ferrara, Ferrara, Italy.
Correspondence to Costanza Emanueli, PhD, Cardiovascular Medicine and Gene Therapy Section, INBB National Laboratory, Viale S. Antonio, 07033 Osilo (SS), Italy. E-mail emanueli{at}yahoo.com
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.
Key Words: proteinase-activated receptor-2 • angiogenesis • skeletal muscle • ischemia
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