Targeting kinin B1 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.