title: Targeting kinin B(1) receptor for therapeutic neovascularization.
abstract: BACKGROUND
  Kinins are modulators of cardiovascular function. After ischemic injury, enhanced kinin generation may contribute in processes responsible for tissue healing.
  
  
  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.
authors.affiliation: Cardiovascular Medicine and Gene Therapy Section, National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.forename: Maria
authors.initials: M
authors.lastname: Bonaria Salis
authors.forename: Tiziana
authors.initials: T
authors.lastname: Stacca
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pintus
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kirchmair
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Isner
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pinna
authors.forename: Leonardo
authors.initials: L
authors.lastname: Gaspa
authors.forename: Domenico
authors.initials: D
authors.lastname: Regoli
authors.forename: Cecile
authors.initials: C
authors.lastname: Cayla
authors.forename: João B
authors.initials: JB
authors.lastname: Pesquero
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000818:Animals; D017209:Apoptosis; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002455:Cell Division; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D005121:Extremities / Q000098:blood supply / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000097:blood / Q000473:pathology / Q000628:therapy*; D017078:Laser-Doppler Flowmetry; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic; D010477:Perfusion; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000819:agonists* / Q000235:genetics; D015398:Signal Transduction
chemical_list: D065168:Bradykinin Receptor Antagonists; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; C072121:bradykinin, Sar-(D-Phe(8))des-Arg(9); C051090:bradykinin, Leu(8)-des-Arg(9)-; D001920:Bradykinin