Protease-Activated Receptor-2 Stimulates Angiogenesis and Accelerates Hemodynamic Recovery in a Mouse Model of Hindlimb Ischemia

Abstract

Abstract-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-NH 2 ) 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-NH 2 ) 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.

Mast Cell Tryptase Stimulates DLD-1 Carcinoma Through Prostaglandin- and MAP Kinase-Dependent Manners

“…Therefore, the mast cells migrating to and accumulating around the cancer tissues may support the growth of cancer cells indirectly through the stimulation of angiogenesis as well as the direct growth promotion via the stimulation of PAR-2. The stimulation of PAR-2 on vascular endothelial cells was also reported to be involved in angiogenesis (23,24). These findings as a whole suggest that mast cells may support colon cancer tissues in two ways: direct proliferation via PAR-2 stimulation and indirect support through angiogenesis.…”

Role of Protease-activated Receptors in the Vascular System

“…The endothelial cells thus appeared to be the primary target of PARs agonist under physiological conditions. PARs are also involved in angiogenesis by endothelial cells (83)(84)(85) and regulation of endothelial barrier function (41)(42)(43)(44)(45). On the other hand, a direct contractile effect of PARs in vascular smooth muscle may play a more important role under pathological conditions such as atherosclerosis (79).…”

Identification of novel VHL targets that are associated with the development of renal cell carcinoma

“…PAR2 (F2RL1) is one of the four known PARs and has been shown to play a role in secretion, smooth muscle contractility, neuromodulation, inflammation, fibrosis, angiogenesis and cancer metastasis (Bertog et al, 1999;Cocks et al, 1999;Danahay et al, 2001;Fiorucci et al, 2001;Hoogerwerf et al, 2001;Richard et al, 2001;Vergnolle et al, 2001;Frungieri et al, 2002;Hollenberg, 2002;Milia et al, 2002). We found that increased PAR2 expression enhanced, and reduced expression decreased, growth of RCC cell lines in vitro, suggesting that upregulation of TMSNB and PAR2 following VHL inactivation contributes to RCC tumorigenesis, although, we note that TMSNB and PAR2 were only upregulated in a proportion of primary RCC with VHL inactivation.…”