Targeting kinin B-1 receptor for therapeutic neovascularization

Background-Kinins are modulators of cardiovascular function. After ischemic injury, enhanced kinin generation may contribute in processes responsible for tissue healing.Methods and Results-Using pharmacological and genetic approaches, we investigated the role of kinin B-1 receptor in reparative angiogenesis in a murine model of limb ischemia. the effect of B-1 pharmacological manipulation on human endothelial cell proliferation and apoptosis was also studied in vitro, Abrogation of B-1 signaling dramatically inhibited the native angiogenic response to ischemia, severely compromising blood perfusion recovery. Outcome was especially impaired in B-1 knockouts that showed a very high incidence of limb necrosis, eventually leading to spontaneous auto-amputation. Conversely, local delivery of a long-acting B-1 receptor agonist enhanced collateral vascular growth in ischemic skeletal muscle, accelerated the rate of perfusion recovery, and improved limb salvage. in vitro, B-1 activation stimulated endothelial cell proliferation and survival, whereas B-1 antagonism induced apoptosis,Conclusions-Our results indicate that the B-1 plays an essential role in the host defense response to ischemic injury. B-1 signaling potentiation might be envisaged as a utilitarian target for the treatment of ischemic vascular disease.INBB Natl Lab, Cardiovasc Med & Gene Therapy Sect, I-07033 Osilo, Sassari, ItalyUniv Sassari, I-07100 Sassari, ItalySt Elizabeths Med Ctr, Boston, MA USAUniv Ferrara, I-44100 Ferrara, ItalyMax Delbruck Ctr Mol Med, Berlin, GermanyUniversidade Federal de São Paulo, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc