Role of bradykinin, nitric oxide, and angiotensin II type 2 receptor in imidapril-induced angiogenesis.
The angiotensin II (Ang II)-Ang II type 1 receptor pathway is proangiogenic, whereas studies showed that some angiotensin-converting enzyme inhibitors also stimulate angiogenesis in the setting of tissue ischemia, leaving a controversy of Ang II-mediated angiogenesis. We investigated whether an angiotensin-converting enzyme inhibitor imidapril-induced angiogenesis might be mediated via the tissue bradykinin pathway. To rule out the conventional effects of Ang II on angiogenesis, we used Ang II type 1a receptor knockout (AT1aKO) mice. We examined the effects of the angiotensin-converting enzyme inhibitor imidapril on angiogenesis in a hindlimb ischemia model using AT1aKO mice. After induction of hindlimb ischemia, AT1aKO mice were treated with or without imidapril (1.0 or 0.1 mg/kg per day for 21 days). Angiogenesis was quantified by laser Doppler blood flowmetry and capillary density. Angiogenesis was reduced in AT1aKO mice compared with wild-type mice. Imidapril with either low or high doses enhanced angiogenesis in AT1aKO mice (P<0.01). Ang II type 2 receptor antagonist (PD123319; 30 mg/kg per day) and B1 receptor antagonist (DesArg9-[Leu8]-bradykinin; 50 nmol/kg per day) suppressed the imidapril-induced angiogenesis in AT1aKO mice to an extent even lower than that of nontreated AT1aKO mice. B2 receptor antagonist (Hoechst 140; 100 microg/kg/d) and NO synthase inhibitor (N(G)-nitro-L-arginine methyl ester; 20 mg/kg per day) moderately attenuated the imidapril-mediated angiogenesis. RT-PCR revealed that vascular endothelial growth factor receptor 2 mRNA was reduced with PD123319, DesArg9-[Leu8]-bradykinin, or Hoechst 140, and vascular endothelial growth factor mRNA abundance was suppressed with PD123319 or DesArg9-[Leu8]-bradykinin. In conclusion, imidapril elicited angiogenesis in the setting of tissue ischemia in AT1aKO mice. This angiogenic effect might involve the Ang II-Ang II type 2 receptor pathway in addition to the bradykinin-B1 and bradykinin-B2 receptor/NO-dependent pathways.
Li
Ping
P
Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-Ku, Nagoya 466-8550, Japan.
Kondo
Takahisa
T
Numaguchi
Yasushi
Y
Kobayashi
Koichi
K
Aoki
Mika
M
Inoue
Natsuo
N
Okumura
Kenji
K
Murohara
Toyoaki
T
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D002196:Capillaries / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines / Q000494:pharmacology*; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
D043925:Angiogenesis Inducing Agents; D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D042461:Vascular Endothelial Growth Factor A; C073402:PD 123319; D009569:Nitric Oxide; C051090:bradykinin, Leu(8)-des-Arg(9)-; C065679:icatibant; C065166:imidapril; D052250:Nitric Oxide Synthase Type III; D040301:Vascular Endothelial Growth Factor Receptor-2; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester