Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia.
BACKGROUND
Human tissue kallikrein (HK) releases kinins from kininogen. We investigated whether adenovirus-mediated HK gene delivery is angiogenic in the context of ischemia.


RESULTS
Hindlimb ischemia, caused by femoral artery excision, increased muscular capillary density (P:<0.001) and induced the expression of kinin B(1) receptor gene (P:<0.05). Pharmacological blockade of B(1) receptors blunted ischemia-induced angiogenesis (P:<0.01), whereas kinin B(2) receptor antagonism was ineffective. Intramuscular delivery of adenovirus containing the HK gene (Ad. CMV-cHK) enhanced the increase in capillary density caused by ischemia (969+/-32 versus 541+/-18 capillaries/mm(2) for control, P:<0.001), accelerated blood flow recovery (P:<0.01), and preserved energetic charge of ischemic muscle (P:<0.01). Chronic blockade of kinin B(1) or B(2) receptors prevented HK-induced angiogenesis.


CONCLUSIONS
HK gene delivery enhances the native angiogenic response to ischemia. Angiogenesis gene therapy with HK might be applicable to peripheral occlusive vascular disease.
Emanueli
C
C
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Rome, Italy.
Minasi
A
A
Zacheo
A
A
Chao
J
J
Chao
L
L
Salis
M B
MB
Straino
S
S
Tozzi
M G
MG
Smith
R
R
Gaspa
L
L
Bianchini
G
G
Stillo
F
F
Capogrossi
M C
MC
Madeddu
P
P
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D065168:Bradykinin Receptor Antagonists; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006614:Hindlimb / Q000098:blood supply* / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D007511:Ischemia / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D016491:Peripheral Vascular Diseases / Q000628:therapy; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020840:Tissue Kallikreins / Q000008:administration & dosage* / Q000235:genetics; D019076:Transgenes / Q000235:genetics
D065168:Bradykinin Receptor Antagonists; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D020840:Tissue Kallikreins