Targeting Kinin B 1 Receptor for Therapeutic Neovascularization

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Abstract
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.