Targeting kinin B-1 receptor for therapeutic neovascularization
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2002-01-22
Autores
Emanueli, C.
Salis, M. B.
Stacca, T.
Pintus, G.
Kirchmair, R.
Isner, J. M.
Pinna, A.
Gaspa, L.
Regoli, D.
Cayla, C.
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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.
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Circulation. Philadelphia: Lippincott Williams & Wilkins, v. 105, n. 3, p. 360-366, 2002.