Targeting kinin B(1) 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.


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.
Emanueli
Costanza
C
Cardiovascular Medicine and Gene Therapy Section, National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Italy.
Bonaria Salis
Maria
M
Stacca
Tiziana
T
Pintus
Gianfranco
G
Kirchmair
Rudolf
R
Isner
Jeffrey M
JM
Pinna
Alessandra
A
Gaspa
Leonardo
L
Regoli
Domenico
D
Cayla
Cecile
C
Pesquero
João B
JB
Bader
Michael
M
Madeddu
Paolo
P
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
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