Protease-activated receptor-2 stimulates angiogenesis and accelerates hemodynamic recovery in a mouse model of hindlimb ischemia.
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.
Cardiovascular Medicine and Gene Therapy Section, National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Sassari, Italy.
Anna F
AF
Milia
Maria B
MB
Salis
Tiziana
T
Stacca
Alessandra
A
Pinna
Paolo
P
Madeddu
Marcello
M
Trevisani
Pierangelo
P
Geppetti
Costanza
C
Emanueli
D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply*; D007273:Injections, Intramuscular; D007511:Ischemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D015854:Up-Regulation
D009842:Oligopeptides; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide