Dual effect of angiotensin-converting enzyme inhibition on angiogenesis in type 1 diabetic mice.
OBJECTIVE
We analyzed the beneficial therapeutic effect of angiotensin converting enzyme inhibitor (ACEI) on both retinal and hind limb neovascularization in diabetic mice.


RESULTS
Diabetic mice (streptozotocin, 40 mg/kg) were treated with or without ACEI (Perindopril, 3 mg/kg per day) or AT1 receptor blocker (Candesartan, 20 mg/kg) for 4 months. Hind limb ischemia was then induced by right femoral artery ligature for 1 additional month. In the ischemic leg, angiographic score, capillary density, and foot perfusion were increased by 2.7, 2.0-fold, and 1.6-fold, respectively, in ACEI-treated diabetic mice compared with untreated diabetic animals (P<0.01). ACEI also raised vascular endothelial growth factor (VEGF) protein level by 1.4-fold in ischemic diabetic leg. This ACEI pro-angiogenic effect was totally blunted in diabetic bradykinin B2 receptor-deficient animals, suggesting that it was mediated by the bradykinin pathway. In the diabetic retina, angiotensinogen and ACE mRNA levels were increased by 2.8-fold and 4.1-fold, respectively (P<0.01 versus nondiabetic mice), highlighting a local activation of renin-angiotensin system. Diabetes also raised VEGF protein level by 1.5-fold (P<0.05 versus nondiabetic mice). Treatments with ACEI and AT1 receptor blocker hampered diabetes-induced VEGF upregulation and retinal neovascularization.


CONCLUSIONS
ACE inhibition improved neovascularization in the diabetic ischemic leg through activation of bradykinin signaling, whereas it reduced vessel growth in the diabetic retina through inhibition of overacting Ang II pathway.
Ebrahimian
Téni G
TG
INSERM U541, Hôpital Lariboisière, IFR Circulation-Lariboisière, Université Paris, France.
Tamarat
Radia
R
Clergue
Michel
M
Duriez
Micheline
M
Levy
Bernard I
BI
Silvestre
Jean-Sébastien
JS
D000792:Angiography / Q000379:methods; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight; D001920:Bradykinin / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects; D007511:Ischemia / Q000378:metabolism; D017078:Laser-Doppler Flowmetry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects; D013311:Streptozocin
D000806:Angiotensin-Converting Enzyme Inhibitors; D012333:RNA, Messenger; D013311:Streptozocin; D007703:Peptidyl-Dipeptidase A; D016283:Proto-Oncogene Proteins p21(ras); D001920:Bradykinin