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(Circulation. 2002;105:360.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Targeting Kinin B₁ Receptor for Therapeutic Neovascularization

Costanza Emanueli, PhD; Maria Bonaria Salis, PhD; Tiziana Stacca, BS; Gianfranco Pintus, PhD; Rudolf Kirchmair, MD; Jeffrey M. Isner, MD; Alessandra Pinna, BS; Leonardo Gaspa, MD; Domenico Regoli, MD; Cecile Cayla, PhD; João B. Pesquero, MD; Michael Bader, MD; Paolo Madeddu, MD

From the Cardiovascular Medicine and Gene Therapy Section, National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Italy (C.E., M.B.S., T.S., A.P., L.G., P.M.); Internal Medicine (P.M.) and Biomedical Sciences (G.P., L.G.), University of Sassari, Italy; Cardiovascular Research, St. Elizabeth’s Medical Center, Boston, Mass, USA (R.K., J.M.I.); Experimental and Clinical Medicine, University of Ferrara, Italy (D.R.); Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany (C.C., M.B.); and Biophysics, Universidade Federal de São Paulo, Brazil (J.B.P.).

Correspondence to Paolo Madeddu or Costanza Emanueli, Cardiovascular Medicine and Gene Therapy Section, INBB National Laboratory, viale Sant’Antonio, 07033 Osilo (Sassari), Italy. E-mail madeddu{at}yahoo.com or emanueli@yahoo.com

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 B₁ receptor in reparative angiogenesis in a murine model of limb ischemia. The effect of B₁ pharmacological manipulation on human endothelial cell proliferation and apoptosis was also studied in vitro. Abrogation of B₁ signaling dramatically inhibited the native angiogenic response to ischemia, severely compromising blood perfusion recovery. Outcome was especially impaired in B₁ knockouts that showed a very high incidence of limb necrosis, eventually leading to spontaneous auto-amputation. Conversely, local delivery of a long-acting B₁ receptor agonist enhanced collateral vascular growth in ischemic skeletal muscle, accelerated the rate of perfusion recovery, and improved limb salvage. In vitro, B₁ activation stimulated endothelial cell proliferation and survival, whereas B₁ antagonism induced apoptosis.

Conclusions— Our results indicate that the B₁ plays an essential role in the host defense response to ischemic injury. B₁ signaling potentiation might be envisaged as a utilitarian target for the treatment of ischemic vascular disease.

Key Words: receptors, bradykinin • angiogenesis • ischemia • muscle, skeletal • endothelium

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