Published online before print August 1, 2002, doi: 10.1161/01.RES.0000031958.92781.9E
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Submitted on April 10, 2002
Revised on July 16, 2002
Accepted on July 22, 2002
Protease-Activated Receptor-2 Stimulates Angiogenesis and Accelerates Hemodynamic Recovery in a Mouse Model of Hindlimb Ischemia
Anna F. Milia ;
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.
* To whom correspondence should be addressed. 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 receptors-2 • angiogenesis • skeletal muscle • ischemia
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